Progress in Neurobiology 67 (2002) 345–391

Role of adrenoceptor subtypes in memory consolidation

Marie E. Gibbs∗ , Roger J. Summers
Department of Pharmacology, Monash University, P.O. Box 13E, 3800 Clayton 3800, Vic., Australia
Received 6 February 2002; accepted 1 July 2002

Abstract
Noradrenaline release in areas within the forebrain occurs following activation of noradrenergic cells in the locus coeruleus (LoC). Release
of noradrenaline by attentional/arousal/vigilance factors appears to be essential for learning and is responsible for the consolidation of
memory.
Noradrenaline can activate any of nine different adrenoceptor (AR) subtypes in the brain and selectivity of action may be achieved by
the spatial location and relative density of the AR subtypes, by different affinities of the different subtypes and by temporal selectivity in
terms of when the different ARs are activated in the memory formation process.
This review examines the use of selective agonists and antagonists to determine the roles of the AR subtypes in the one-trial discriminated
avoidance learning paradigm in the chick. A model is developed that integrates noradrenergic activity in basal ganglia (lobus parolfactorius
(LPO)) and association cortex (intermediate medial hyperstriatum ventrale (IMHV)) leading to the consolidation of memory 30 min after
training. There is evidence that ␤2 - and ␤3 -ARs are important in the association area but require input from ␣2 -AR stimulated activity in
the basal ganglia for consolidation. On the other hand, ␣1 -AR activation in the IMHV is inhibitory and prevents consolidation. While there
is no role for ␤1 -ARs in memory consolidation, they play a role in short-term memory (STM). The use of the precocial chick has clear
advantages in having a temporally discrete learning task which allows for discrimination memory and whose development can be followed
at discrete intervals after learning. These studies reveal clear roles for AR subtypes in the formation and consolidation of memory in the
chick, which have allowed the development of a model that can now be tested in mammalian systems.
© 2002 Elsevier Science Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
1.1. The importance of noradrenaline to memory formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
1.2. Source of the noradrenergic stimulus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
1.2.1. Afferent input . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
1.2.2. Efferent output . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
1.3. Involvement of noradrenaline in arousal and reinforcement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
1.3.1. Arousal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
1.3.2. Reinforcement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
1.4. Physiological action of noradrenaline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
1.5. Behavioral pharmacology of noradrenergic manipulation of memory formation—enhancement
and inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
2. A model of memory formation in the chick . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
2.1. Justification for the use of chicks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
2.2. Discriminated avoidance learning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
2.2.1. Description of the learning task . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
2.2.2. Behavioral evidence for the memory model with strongly reinforced learning . . . . . . . . . . . 352
2.2.3. Behavioral evidence for the memory model with weakly reinforced learning . . . . . . . . . . . . 352

Abbreviations: AR, adrenoceptor; hem, hemisphere; IMHV, intermediate hyperstriatum ventrale; ITM, intermediate memory; LoC, locus coeruleus;
LPO, lobus parolfactorius; LTM, long-term memory; STM, short-term memory
∗ Corresponding author. Tel.: +61-3-9905-1440; fax: +61-3-9905-8192.

E-mail address: marie.gibbs@med.monash.edu.au (M.E. Gibbs).

0301-0082/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S 0 3 0 1 - 0 0 8 2 ( 0 2 ) 0 0 0 2 3 - 0
346 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391

2.3. Development of the chick model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353

2.3.1. The use of drugs to modify memory storage processes—rationale for time of
injection and time of test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
2.3.2. Foundation for the chick memory model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
2.3.2.1. Inhibition of memory processing with strongly reinforced training . . . . . . . . . . . . 353
2.3.2.2. Enhancement of memory formation using weakly reinforced training . . . . . . . . . 355
2.3.2.3. Pharmacological specificity rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
2.3.2.4. Dose–response relationships . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
2.3.3. Injection procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
3. Anatomy of the chick brain with respect to memory studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
3.1. Function of brain areas implicated in memory storage in the chick. . . . . . . . . . . . . . . . . . . . . . . . . .359
3.2. Distribution of noradrenergic fibers and cell bodies in avian brain . . . . . . . . . . . . . . . . . . . . . . . . . . 360
3.3. Distribution of adrenoceptor subtypes in avian brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
4. Identification of the AR subtypes responsible for the action of noradrenaline on memory
consolidation in the chick. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .361
4.1. The effect of intracranial injection of noradrenaline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
4.2. Modification of action of noradrenaline on memory consolidation in the IMHV by
different AR subtype antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362
4.3. ␣2 -Adrenoceptor involvement in the action of noradrenaline in LPO . . . . . . . . . . . . . . . . . . . . . . . . 364
4.4. Action of a selective ␤-adrenoceptor agonist—isoprenaline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364
4.5. Inhibition of memory consolidation by high doses of noradrenaline . . . . . . . . . . . . . . . . . . . . . . . . . 364
4.6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364
5. ␣1 -Adrenoceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366
5.1. Inhibition of memory for strongly reinforced learning by ␣1 -adrenoceptor agonists . . . . . . . . . . 366
5.2. Specificity of action of ␣1 -adrenoceptor agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366
5.3. Consolidation of labile, weakly reinforced, memory by ␣1 -adrenoceptor antagonists . . . . . . . . . 367
5.4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
6. ␣2 -Adrenoceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
6.1. ␣2 -Adrenoceptor agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
6.2. Specificity of action of ␣2 -adrenoceptor agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
6.3. ␣2 -Adrenoceptor antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370
6.4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371
7. ␤2 -Adrenoceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
8. ␤2 -Adrenoceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
8.1. Consolidation of labile, weakly reinforced memory by the ␤2 -adrenoceptor agonist zinterol . . 372
8.2. Specificity of the action of zinterol on ␤2 -adrenoceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373
8.3. Inhibition of strongly reinforced memory by the ␤1+2 -adrenoceptor agonist propranolol . . . . . . 373
8.3.1. Subcutaneous administration of propranolol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373
8.3.2. Intracranial administration of propranolol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
8.4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
9. ␤3 -Adrenoceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
9.1. Consolidation of labile, weakly reinforced, memory by ␤3 -adrenoceptor agonists . . . . . . . . . . . . 376
9.2. Specificity of action of ␤3 -adrenoceptor agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
9.3. Inhibition of memory formation by ␤3 -adrenoceptor antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379
9.4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379
10. Peripheral administration of noradrenaline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
11. Summary of the action of different adrenoceptors at different times and in different
brain locations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382
11.1. Consolidation of memory by administration of noradrenaline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382
11.2. Involvement of ␤2 - and ␤3 -adrenoceptors in IMHV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382
11.3. Involvement of ␤2 - and ␤1 -adrenoceptors in the basal ganglia (LPO) . . . . . . . . . . . . . . . . . . . . . . 383
12. Hypothesis for the role of noradrenaline in memory consolidation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .384
12.1. Consequences of activation of adrenoceptors to memory formation . . . . . . . . . . . . . . . . . . . . . . . . 384
12.1.1. Metabolic consequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384
12.1.2. Physiological consequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384
12.1.3. Psychological consequences. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .384
12.2. Interactions of noradrenaline with hormones and other neurotransmitter systems . . . . . . . . . . . . 385
12.3. Noradrenaline and cognitive diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385
13. General conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386
 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
1. Introduction
This is an idiosyncratic review summarizing work done
on the action of noradrenaline and adrenoceptor (AR) ago-
nists and antagonists on memory consolidation primarily in
the chick. It is not our objective to comprehensively review
the extensive literature on the involvement of noradrenaline
in memory formation, but to put a particular point of view
as to how noradrenaline acts on different ARs, and how this
relates to memory processing in the chick. There are two im-
portant periods in memory processing where noradrenaline
plays a role. The first occurs at the time of acquisition, where
attentional or arousal factors are important and are related
to noradrenaline release; the second occurs at the time of
consolidation, the time when labile memory is stored into a
permanent form. Without noradrenergic involvement, mem-
ory formation or consolidation do not occur. Noradrenergic
cell bodies in the locus coeruleus (LoC) innervate the key
areas in the forebrain and therefore will be important in
orchestrating the processes determining the formation and
consolidation of memory. In this review the involvement
of noradrenaline in memory formation is illustrated using
a single-trial discriminated learning task in the chick. It is
likely that the principles will apply equally to mammalian
memory storage.
Information or ‘stimulus response connections’ may
be stored in the brain, depending on the significance or
consequences of the response; whether the mechanism
of storage is by physiological effects such as long-term
potentiation or depression is not yet clear and is not the
subject of this review. Noradrenaline is believed to be im-
portant in determining whether or not the information is
stored and selectivity can be achieved through the AR sub-
types involved. The role of noradrenaline has often been
regarded as being modulatory or ‘permissive’ in determin-
ing the maintenance of the information (Bloom, 1984).
Undoubtedly there are many other influences on memory
storage provided by cholinergic, GABAergic and other
neurotransmitter systems and local circuit neurones influ-
encing the storage of memory. Inhibition of memory can
be achieved by disruption of any of these components, and
complex interactions can be shown to exist between these
components (e.g. between nitric oxide and glutamate and
noradrenaline).
There are at least nine different ARs present in the central
nervous system and, as these receptors are normally acti-
vated by a single neurotransmitter, noradrenaline, this multi-
plicity of recognition sites can only be functionally relevant
to memory formation if stimulation results in the activation
of distinct messages via the receptors, perhaps in different
locations and at specific times in the memory processing
sequence. Our hypothesis is that noradrenaline will have
different actions in modulating memory formation depen-
dent on the populations of ARs in different brain locations
and at different times in the sequence of memory processing.
Two brain areas have been investigated to date and there are
347
undoubtedly other areas in the brain where noradrenaline
could influence memory formation. That noradrenaline has
different effects depending on the site of injection empha-
sizes the potential difficulty in interpretation of the effect
of any AR agonist or antagonist given systemically.
This line of research was prompted by the discovery of
mRNA for ␤3 -ARs in rat brain, in particular in the cortex,
hippocampus and hypothalamus (Summers et al., 1995),
which stimulated the search for functional roles for central
␤3 -ARs. Since noradrenaline released in the brain has mul-
tiple roles in brain function acting through AR subtypes
that are widely distributed in the brain, it became necessary
to dissect out the roles of the other AR subtypes in memory
formation.
1.1. The importance of noradrenaline
to memory formation
The early hypotheses implicating noradrenaline in mem-
ory formation can be seen in reviews by Seymour Kety in
the 1970s (Kety, 1970, 1972), which suggested that nora-
drenaline, and perhaps other biogenic amines, were released
in affective states such as arousal and were the reinforcing
stimulus responsible for the subsequent storage of memory.
Kety proposed, “The aroused state induced by novel
stimuli, or by stimuli genetically recognized as significant,
is pervasive and affects synapses throughout the central
nervous system, suppressing most, but permitting or even
accentuating activity in those that are transmitting the novel
or significant stimuli.” The aroused state or significant state,
which is associated with the release of noradrenaline, selec-
tively acts on neurones that are actively involved at the time
of learning and ensures the consolidation into permanent
memory. Kety’s original suggestion was that environmental
information represented by actions of classical neurotrans-
mitters would be enhanced by noradrenaline (Harley, 1987).
Kety defined “arousal as a basic emotion, a generalized
state that is associated with, and facilitates, recognition and
exploration of novel and significant stimuli.” Noradrenaline
is involved in the mediation of this state.
Arousal is a vague behavioral concept, which is produced
by a number of different factors. It covers a range of behav-
iors from wakefulness, attention, vigilance to fear and stress,
as well as motivational factors, such as hunger and thirst.
Gold and McGaugh (1975) proposed a similar hypoth-
esis, whereby “an experience establishes a memory trace
that is transient (soon forgotten) unless the non-specific
physiological response to an experience establishes a
brain state that promotes memory storage processes.” This
non-specific physiological response may be a change in
arousal or hormonal levels, which continue for some time
after the experience. Normally reinforcing stimuli such as
food or electrical footshock contribute to both the specific
and non-specific physiological responses.
There is a general consensus that noradrenaline is a
necessary and important component of memory formation
348 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
and consolidation, although other neurotransmitter systems
(serotonin, acetylcholine, GABA as well as substance P,
vasointestinal polypeptide, etc.) are also involved and are
capable of modulating memory formation.
It is possible that there are many ways to influence or
modulate memory storage and there are also multiple brain
memory systems (e.g. amygdala, hippocampal and cortical
memory systems), which undoubtedly interact depending on
the situation at the time of learning and interactions between
existing memories in the brain. However, it is generally
accepted that noradrenaline plays an extremely impor-
tant role in attention, arousal, memory consolidation and
retrieval (e.g. Foote et al., 1991; Sara, 1998; Usher et al.,
1999).
1.2. Source of the noradrenergic stimulus
In the mammalian and the avian central nervous system,
the noradrenergic axons innervating the neocortex, hip-
pocampus and cerebellum originate from a small group of
noradrenergic cells clustered in the dorsal pons, the A6 or
LoC. There are other noradrenergic nuclei in the brainstem,
with more limited projections that target regions of the
hypothalamus, certain limbic nuclei and the spinal cord. The
LoC noradrenergic system was viewed as a broadly pro-
jecting system with non-specific functions. This was partly
based on the early findings that indicated that LoC efferent
projections were widespread, that single LoC neurones sent
divergent projections to target cells of very different func-
tion, and that the nucleus was not topographically organized
in a manner that could confer specificity (Valentino and
Aston-Jones, 1995). However, there is considerable speci-
ficity in the response of the LoC to various stimuli and in
its effect on different target neurons.
1.2.1. Afferent input
The LoC itself receives a very restricted set of inputs
from two rostral medullary nuclei (the paragigantocellularis
and the prepositus hypoglossi), but afferents from areas
previously thought to innervate the LoC, including the pre-
frontal cortex, amygdala and hippocampus, go to structures
surrounding the LoC (Foote et al., 1983; Aston-Jones et al.,
1991). The key analyses that determine LoC firing must
therefore be carried out in higher centers (Aston-Jones
et al., 1986). Many neurotransmitters are involved in the
innervation of the LoC and are found in the neurons of the
two major LoC afferents, including adrenaline, glutamate,
enkephalin, corticotrophin-releasing factor, substance P,
serotonin and GABA (Valentino and Aston-Jones, 1995).
The release rates of these various neurotransmitters are
modified by arousing and stressful stimuli (Singewald and
Philippu, 1998). A prominent indirect connection between
the circadian oscillator of the suprachiasmatic nucleus and
the LoC suggests a mechanism for regulation of sleep-
ing and waking and the circadian regulation of cognitive
abilities (Aston-Jones et al., 2001).
1.2.2. Efferent output
The LoC is the sole source of noradrenaline in the
hippocampus and the neocortex, as well as a major con-
tributor to other regions (Foote et al., 1983). The pattern
of monoaminergic terminals from the LoC innervating
the cortex shows regional specificity with a distinct lami-
nar distribution in different areas of cortex (Morrison and
Magistretti, 1983; Papadopoulos and Parnavelas, 1991).
A single LoC neurone can project to different cortical
hemispheres (hems), to hippocampus and cortex, to thalamus
and cortex, to thalamus and hippocampus and to forebrain
and spinal cord. It has been suggested, “this divergence sup-
ports the idea that changes in LoC discharge can simultane-
ously impact on functionally diverse targets, and this could
be one way in which the LoC could coordinate the activity
of multiple systems.” (Valentino and Aston-Jones, 1995).
It was originally thought that noradrenergic terminals
in the cerebral cortex did not make synaptic contacts, but
rather existed in non-synaptically arranged terminals to pro-
vide noradrenaline in a paracrine fashion. However, there is
now considerable evidence for conventional synaptic trans-
mission at many of the terminations (Foote et al., 1983;
Papadopoulos and Parnavelas, 1991). It is also possible that
both synaptic and paracrine modes of neurotransmission
exist at the same or different NE terminals (Valentino and
Aston-Jones, 1995). There is also evidence that, as well as
interacting with neurones, noradrenaline may interact with
astrocytes via ␤-ARs (e.g. Aoki, 1992; Shao and McCarthy,
1994; Stone, 1994; Mantyh et al., 1995). Noradrenergic
terminals are also associated with intraparenchymal blood
vessels in the frontoparietal cortex (Cohen et al., 1997). It
is clear that there are a number of possible ways in which
noradrenaline could effect memory formation.
1.3. Involvement of noradrenaline in
arousal and reinforcement
1.3.1. Arousal
There is dense noradrenergic innervation from the LoC
to the thalamic reticular nucleus that coordinates thalam-
ocortical activity (Foote et al., 1983). The effects of LoC
stimulation or noradrenaline administration on thalamic
neuronal activity have been one of the better-characterized
post-synaptic effects of this system. These effects suggest
a model whereby LoC activation can produce a shift from
drowsiness to the alert state, (see Foote and Aston-Jones,
1995). Arousal has variously been regarded as the transi-
tion between sleep or unconscious states and wakefulness,
conscious awareness or the effective cortical processing of
information. Sarter and Bruno (2000) draw a distinction
between specific attentional functions, such as selective,
sustained and divided attention performance in cortical
projections and arousal-induced attentional processing (i.e.
stimulus detection, selection and processing as a result of
a novel, highly salient, aversive or incentive stimuli). The
latter are mediated by brainstem ascending noradrenergic
 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
projections to the basal forebrain, which in turn activate or
‘recruit’ the cortical afferent circuits. ‘Arousal’ is not uni-
tary but quite a complex concept, but is generally associated
with noradrenergic activation (Robbins, 1997).
1.3.2. Reinforcement
Traditionally, memory was something that is determined
by, and thus follows reinforcement (Huston et al., 1977).
In simple terms, the stimulus is presented to an animal, the
animal responds to that stimulus and the reinforcer acts by
some consequence of the response to result in an increased
probability of that stimulus producing the same response in
the future, i.e. reinforcement and the storage of the mem-
ory. Noradrenaline has been implicated in the action of the
reinforcer or the reinforcing stimulus on memory formation,
even if the reinforcer is not always identifiable. The function
of arousal, attention, etc. in releasing noradrenaline may be
to supply the reinforcing signal leading to consolidation of
the memory.
The link between neuronal activity in the LoC and target
cell effects (i.e. noradrenaline release), demonstrates that
stimuli that are known to increase LoC firing rate, also in-
crease noradrenaline levels in extracellular fluid or increase
the noradrenaline signal as measured by voltammetry in
post-synaptic targets (cortex, hippocampus and thalamus) of
the LoC–noradrenaline system. These stimuli include foot-
shock, restraint stress, electrical and chemical stimulation
of the LoC or dorsal noradrenergic bundle (see Berridge
and Abercrombie, 1999).
1.4. Physiological action of noradrenaline
Early investigations into the effect of applied nora-
drenaline on the cortex revealed a generalized inhibition of
neuronal activity in the target cells. This occurred in a num-
ber of other brain areas and suggested a global effect of the
LoC–noradrenergic system in inhibition (Foote et al., 1983).
However, there is a concentration-dependent effect, where
low doses selectively enhance the effects of afferent inputs
relative to basal or spontaneous discharge, while higher
concentrations result in inhibition.
These effects led to the idea that LoC activation increases
the signal-to-noise ratio of activity in post-synaptic neu-
rones, suggesting that the LoC–noradrenaline system func-
tioned to increase processing of information about incoming
sensory stimulation, as opposed to solely altering basal
discharge rate (Foote et al., 1983); increasing the signal-to-
noise ratio. This would selectively enhance responses to
discrete signals while inhibiting background spontaneous
‘noise’ (Aston-Jones, 1985).
Another mechanism where noradrenaline can modulate
central activity is suggested by a ‘gating’ action of nora-
drenaline, whereby weak or subthreshold synaptic stimuli
can evoke threshold neuronal responses in the presence of
iontophoretically applied noradrenaline or following elec-
trical stimulation of the LoC (Waterhouse et al., 1988).
349
Threshold excitatory and inhibitory synaptic inputs may
normally arrive at central neurones but not trigger a re-
action except during behavioral conditions favoring the
synaptic release of noradrenaline. There is now consider-
able evidence that noradrenaline is also able to modulate
long-term potentiation in the hippocampus (e.g. Hopkins
and Johnston, 1984; Harley, 1987, 1991; Harley, 1998).
The presence of noradrenaline can change the mode of
activity of thalamic neurones from burst to spike. In the
awake animal, phasic alterations in discharge rates of the
LoC are observed in response to salient sensory stimuli (Sara
et al., 1994; Berridge and Abercrombie, 1999). LoC cells
respond in burst to imposed novel sensory stimuli or to novel
objects encountered during free exploration. Rapid habitua-
tion of the LoC response occurs when there is no predictive
value of the stimulus or no behavioral response is required.
When a stimulus is associated with reinforcement, there is
a renewed but transient response. Thus, cells in the LoC re-
spond to novelty or change in incoming information, but do
not have a sustained response to stimuli, even when they
have a high level of biological significance. The gating and
tuning action of noradrenaline released in target sensory sys-
tems would promote selective attention to relevant stimuli at
the critical moment of change (Sara et al., 1994; Waterhouse
et al., 1988).
1.5. Behavioral pharmacology of noradrenergic
manipulation of memory formation—enhancement and
inhibition
From the early 1970s there was a flood of work on the
involvement of noradrenaline in memory formation, many
of which involved lesions, physical or pharmacological,
with drugs like 6-hydroxydopamine. Bammer reviews over
100 studies on noradrenergic influences on passive avoid-
ance learning tasks in rats and mice up to 1981 (Bammer,
1982).
Pennartz (1996) considered the involvement of nora-
drenaline, acetylcholine and dopamine as neuromodulators
responsible for reinforcement and concluded that behavioral
studies, including those that depleted noradrenaline with
6-hydroxydopamine, do not support the view that nora-
drenaline has a specific function as a reinforcement signal.
“Furthermore, well characterized pre- and post-synaptic ef-
fects of noradrenaline compromise a role for noradrenaline
as a simple multiplicative factor in learning rules.” How-
ever, with inhibitory studies for example, there are a number
of variables to be considered including whether the drug
is administered before or after learning, the actual time at
which the drug is given, the route of administration, the
dose/dose range employed; when the animal is tested and
also the nature of the response. Regarding the latter, it is
important to include appropriate controls to ensure that the
result cannot be interpreted as an effect on performance.
For example, if the drug inhibits activity in a passive avoid-
350 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
ance paradigm, this could be construed as no effect because
memory is measured as no response; alternatively, if the
drug inhibits activity in an active avoidance paradigm, this
would be interpreted as an effect because no response in
this situation would mean no memory.
There is a considerable amount of evidence for the
involvement of noradrenaline and ARs in learning and
memory. For example, noradrenaline enhances memory
formation when administered into various brain regions in-
cluding the hippocampus and entorhinal cortex (Izquierdo
et al., 2000); and amygdala (Liang et al., 1986; Hatfield and
McGaugh, 1999; Clayton and Williams, 2000). Brain con-
centrations of noradrenaline after training have been corre-
lated with retention performance and peripheral adrenaline
modulation of memory processing (Gold and van Buskirk,
1978); noradrenaline release in the hippocampus during
spontaneous alternation tests (Men et al., 1999); and in
the amygdala in response to footshock stimulation (Galvez
et al., 1996).
Experiments demonstrating the enhancement of memory
formation by peripherally administered adrenaline (Sternberg
et al., 1985a; Liang et al., 1990; Liang et al., 1995) or
centrally administered noradrenaline (Liang et al., 1995;
Hatfield and McGaugh, 1999) show that this enhancement
can be prevented by different AR antagonists. Recent work
involving the use of adrenergic receptor agonists and antag-
onists has provided support for the notion of adrenergic in-
volvement in memory consolidation. Administration of the
␤-noradrenergic antagonists propranolol, ICI 118,551, timo-
lol and sotalol have all been shown to impair the acquisition
of memory in a variety of tasks in both rats (Sullivan et al.,
1991; Lennartz et al., 1996; Izquierdo et al., 1998; Cahill
et al., 2000; Sullivan et al., 2000) and chickens (Stephenson
and Andrew, 1981; Davies and Payne, 1989; Stephenson,
1991). Conversely, activation of ␤-adrenergic receptors
with agonists such as isoprenaline (Sullivan et al., 2000)
clenbuterol (Ferry and McGaugh, 1999) and salbutamol
(Crowe and Shaw, 1997) enhance memory retention. The
inhibitory effect of the noradrenaline depleting toxin DSP-4
in chicks (Davies et al., 1985; Crowe and Shaw, 1997) can
also be prevented by noradrenaline or by the ␤2 -AR agonist
salbutamol (Crowe and Shaw, 1997). Izquierdo et al. (1998)
have found differential effects of noradrenaline on STM
and LTM in the entorhinal cortex or hippocampus.
There is less information regarding the involvement of
␣-ARs in memory formation. With intra-amygdala infu-
sion prazosin impaired memory retention at three different
doses (0.1–1.0 ␮g) (Ferry et al., 1999b) and when phenyle-
phrine was infused together with yohimbine and atenolol
(a ␤-AR antagonist) the resulting improvement in mem-
ory was attributed to an effect on ␣1 -ARs. These authors
also suggest that the action of noradrenaline on ␣1 -ARs in
the basolateral amygdala occurs via modulation of ␤-AR
effects (Ferry et al., 1999a). Infusion of the ␣1 -AR antag-
onist prazosin attenuated the enhancement of memory by
the ␤-AR agonist clenbuterol. A different role for the two
␣-ARs in the prefrontal cortex is suggested by Arnsten’s
group (Arnsten, 1998b, 2000), where she describes oppo-
site actions of ␣1 - and ␣2 -AR agonists on spatial working
memory (delayed-response performance). The ␣2A -AR
agonist guanfacine improved memory, an effect reversed
by the ␣2A -AR antagonist idazoxan. On the other hand,
the ␣1 -AR agonist cirazoline impaired delayed-response
performance, an effect blocked by the ␣1 -AR antago-
nist prazosin. However, cirazoline did not impair perfor-
mance if there was no delay between the stimulus and
response. Again, the response to activation of different
AR subtypes depends on the location of the action in the
brain.
The involvement of noradrenaline in memory storage will
probably be different and involve different ARs in different
locations in the brain depending on the nature of the involve-
ment of these different locations. Many parts of the brain
contribute to learning, but each in a different and specific
way. As Young (1979) concluded, the critical changes for
learning may take place in one or a few places, but they are
only made effective with the essential cooperation of other
areas of the brain that will probably differ depending on the
nature of the task to be learned; with the involvement of
different neurotransmitters and/or different transmitters and
their different receptor subtypes.
Sara (1998) argues, “ the importance of the behavioral
situation, attentional demands of the task, and stimulus-
reinforcement contingencies” are critical in promoting or
permitting experience-dependent neuronal plasticity. As
an example, specific activation of the LoC noradrener-
gic system occurs with novel stimuli encountered while
investigating the environment and also during formal learn-
ing situations. The response of the noradrenergic neu-
rones is concerned with changes in the predictive value
of the stimulus determining when new learning should
occur.
If noradrenergic modulation during memory formation is
to be appropriately related to what has to be learned, it
must somehow vary at the appropriate times and places to
specifically affect only the information to be learned. One
possible mechanism is that events instigated at the time of
acquisition include an appropriate influence neuronal fir-
ing in the LoC. If the learning experience is assessed as
important as a result of analysis, and noradrenergic activ-
ity is centrally commanded, then this would modulate the
neural trace of the information to be stored. It is argued
that there is a noradrenergic influence at the time of learn-
ing, reflected in attentional, arousal influences from the LoC
or even short-term learning. This results in a labile mem-
ory; memory lasting in the present learning paradigm for
30 min. After this time, if the appropriate reinforcement
mechanisms, consisting of additional noradrenaline release,
do not take place then the memory is not consolidated into
long-term storage. The second release of noradrenaline is
required after a longish delay and in the absence of external
causation.
 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
2. A model of memory formation in the chick
A memory model with sequential stages was put forward
in 1972 (Mark and Watts, 1971; Watts and Mark, 1971a,b)
by following the development of memory after a single
10 s learning experience. By testing for memory at different
times after the initial learning experience, it was possible to
show three different stages of memory (Fig. 1). These stages
were first defined on the basis of their vulnerability to in-
terference by different pharmacological agents. The stages
were sequentially dependent, of defined duration and each
was revealed by prevention of the following stage. Thus,
intermediate memory (ITM) was revealed by prevention of
long-term memory (LTM) and short-term memory (STM)
was revealed by prevention of ITM (Gibbs and Ng, 1976b,
1977). The question raised at the time was whether testing of
chicks without any inhibitory drugs would reveal evidence
of the different stages of memory. It became evident that
there are periods in the retention time course where there
is apparently no memory present. These are represented by
the ‘dips’ in retention at the times predicted for the cross
over of the different stages as determined from pharmaco-
logical studies (Gibbs and Ng, 1979a) (see Section 2.2).
Theoretically, this memory model represents the memory
stages that occur in any one animal over time after training.
2.1. Justification for the use of chicks
There a number of reasons why the chick is an ideal
model for the study of basic cellular processes in memory
formation apart from the practical consideration of housing
and cost of animals. Chicks do not need to be housed for
long periods and are suitable to train on arrival in the labo-
ratory. The chicks are males from an egg laying breed with
no commercial value and therefore are relatively inexpen-
Fig. 1. Schematic representation of memory stages based on performance
tested at discrete times after training. Good memory is represented by
a disc. ratio approaching 1.0 and chicks avoid the red bead. With poor
memory the disc. ratio approaches 0.5 and the chicks peck both beads
equally. The ‘dips’ in retention, where the chicks ‘appear’ to forget the
aversive taste on the bead and peck define the different stages in memory
formation. ITM can be further divided into phases A and B on both
behavioral and pharmacological grounds.
351
sive. Chicks can be obtained from one hatch in the numbers
needed to complete an experiment. Day-old chicks are
naı̈ve, certainly with respect to red and blue beads, which
means the chick has very little conflicting or confusing in-
formation that may be found in animals, such as rodents,
that take time to develop post-natally. However, the innate
behavior of pecking at small objects of food size is essential
to the exploration of the environment to develop feeding
behaviors.
The use of one-trial learning gives an accurate measure-
ment for the time of learning. Working with groups of 20 and
allowing 15 s for each pair of chicks, training, testing and
injections can be made with an accuracy of within 15 s. This
has allowed for accurate and detailed time-courses of injec-
tion and retention testing of memory over a range of times.
Detailed dose–response relationships can be constructed
and challenges made to examine shifts of dose–response
relationships. The details of when to inject, what dose and
what route require a large number of animals to determine
the basic data. This sort of detail cannot be worked out for
rodents without the use of a large number of animals and
hence becomes very expensive. There seems no a priori rea-
son why chicks should be any different in the basic memory
mechanisms to rodents or primates; indeed chicks may be
a more appropriate model to work with than nocturnal ro-
dents. The procedures outlined in this paper were approved
by the Monash University Animal Ethics Committee and
comply with the 1997 Australian Code of Practice for the
Care and Use of Animals for Scientific Purposes.
2.2. Discriminated avoidance learning
The original experiments used a passive avoidance train-
ing task, where memory was scored as avoidance of the
target bead in a 10 s period, although the ability of the
chicks to discriminate between different colored targets was
demonstrated (Mark and Watts, 1971). In 1976 (Gibbs and
Barnett, 1976; Gibbs and Ng, 1977) a learning task involv-
ing discrimination of targets to peck at rather than simple
avoidance (peck or no peck) was introduced.
2.2.1. Description of the learning task
The findings outlined in this review are based on the abil-
ity of chicks to discriminate between two different colored
beads, one of which is dipped in a bitter tasting chemical—
methyl anthranilate. The chicks associate the bitter taste with
one of the colors (red) and refuse to peck at that color on
subsequent presentations, but at the same time they will peck
at a different color (blue). This task utilizes an innate behav-
ioral response of chickens, that of pecking at small objects.
Chicks in the first few days of life have to discriminate be-
tween food and non-food items. There is a period of around
4 days after hatch, where experimentation by the chick is
essential to learning about the environment, with the resid-
ual yolk sac supplying nutrients, until they determine what
is food.
352 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
Day-old male chicks from an egg laying strain (White
Leghorn × Black Australorp) obtained from a local hatchery
on the morning of each experiment are kept in pairs. Chicks
in groups of 20 are presented with beads to peck at in or-
der to accustom them to foreign objects. The first two bead
presentations are of small, shiny, wet, metal beads followed
by two other trials where larger red and blue glass beads,
also dipped in water, are presented. The latency to first peck
and the number of pecks at these colored beads in 10 s are
recorded. For training 30 min later, the red bead is dipped
into a bitter tasting chemical aversant—methyl anthranilate,
and the birds are presented with this bead in the same man-
ner as in the previous trials. Retention of memory for the
aversive taste on the red bead is tested at various times after
training by re-presenting the original (but now dry) red and
blue beads in successive trials—allowing the pair of chicks
10 s to either peck the bead or to avoid it. If the chicks re-
member that the red bead once had the bitter tasting chemi-
cal on it, then they will avoid the bead or peck only a small
number of times compared to the number of pecks they make
to the blue bead. If the chicks completely forget that the bead
tasted bitter on training, then they will peck equally at both
red bead and blue beads. This information is used in the cal-
culation of the memory retention score—the discrimination
ratio (disc. ratio), which is the number of pecks on the blue
bead compared to the number of pecks on the red and the
blue bead. If a chick remembers, it will have a disc. ratio
close to 1.0; if it forgets then it will approach 0.5 (see Fig. 1).
An individual disc. ratio is obtained for each chick and the
data are presented as mean and S.E.M. Seven-day-old chicks
have a retention time course the same as that seen in Fig. 2B
(unpublished observations). In the experiments reported here
testing is made up to 120 min after training.
2.2.2. Behavioral evidence for the memory model with
strongly reinforced learning
When separate groups of chicks are tested at different
intervals up to 120 min after training, commencing 5 min
Fig. 2. Disc. ratios of pecks at red and blue beads representing retention levels following: (A) weakly reinforced training with 20% anthranilate; and (B)
strongly reinforced training with 100% anthranilate.
after training on concentrated anthranilate, memory retention
(measured as the mean disc. ratio), remains high except for
tests conducted at 15 and 55 min after training (Fig. 2B).
2.2.3. Behavioral evidence for the memory model with
weakly reinforced learning
There is a valuable modification that can be made to the
original paradigm. If the aversant used on the training trial is
diluted with alcohol, so that 20% anthranilate is used rather
than 100%, the chicks remember to avoid the red bead for
a short period of time (generally 30 min), but the memory
then disappears and the chicks will again peck at the red
bead on subsequent presentation. The memory goes through
the STM and ITM stages until 30 min and then fades, with
consolidation not progressing any further (Fig. 2A).
Because chicks will peck 15 min after training (first dip),
it was possible to increase the number of training trials and
it was found that 0.25% anthranilate (Gibbs et al., 1991) or
10% anthranilate (Crowe et al., 1989a) produced consoli-
dation after four trials. It is of interest that increasing the
number of trials resulted in progressively longer duration
of the first part of ITM (ITM.A) until ITM.B commenced
and consolidation occurred (Crowe et al., 1991b). With
stronger levels of anthranilate (20%) on the bead during
training, only two trials were needed to promote consoli-
dation of memory. This weakly reinforced version of the
discriminated avoidance task has become a valuable tool
for investigating pharmacological ways of promoting the
consolidation of memory.
Chicks kept in isolation show an increased duration of
STM (Gibbs and Ng, 1979a) an altered pattern of memory
loss to amnestic drugs (de Vaus et al., 1980) and increased
levels of plasma corticosterone (Gibbs and Ng, 1984b).
Isolation for even 1 h following training consolidates weakly
reinforced learning (Johnston and Rose, 1998). Stress in-
duced increases in corticosterone or even noradrenaline are
the possible cause of the consolidation. Chicks are normally
not tested more than once to avoid the possibility of
 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
contaminating the original memory. In one set of experi-
ments where the chicks were tested twice (Gibbs, 1982),
first at the time of the 15 or 55 min ‘dip’ and then tested
again 180 min after training, the performance on the second
test reflected the reinforcer on the bead the first time. When
the chicks were presented with a clean, dry bead at 15 or
55 min, 180 min after training they avoided the red bead.
If the bead was dipped in water at 15 or 55 min, on test
180 min after training, the chicks pecked at the red bead.
The consequence of now knowing that the bead no longer
tastes aversive resulted in a change in the response to red
beads. The ‘dips’ in retention may provide a time period
when an animal can ‘change its mind’. When the chicks
were tested even 5 min after the 15 min test, they will either
avoid the bead or peck at it depending on whether it was
dry or wet on the first test (Gibbs, 1982).
2.3. Development of the chick model
As mentioned previously this model was originally
developed from information obtained by varying the time
of injection of different classes of drugs which produced
amnesia at a set time after training (usually 2, 3 or 24 h). A
second protocol was developed where the time of adminis-
tration was kept constant and the chicks tested at different
times after training to see where memory loss first occurred.
2.3.1. The use of drugs to modify memory storage
processes—rationale for time of injection and time of test
It has been argued that if a drug is only amnestic when
injected before training the result may in fact be caused by
an effect on acquisition/perception (e.g. McGaugh, 1989).
Consequently, many studies have restricted drug injections
to post-learning periods. The most important piece of in-
formation from these time of injection studies is the time
at which susceptibility to the drug ceases, assuming that
the drug is capable of inhibiting as soon as it is injected.
Although it has also been argued that the time at which an
administered drug is effective does not necessarily reflect
the timing of involvement of the biochemical or physiolo-
gical process being inhibited. For example, a drug may be
effective in producing amnesia when injected from 30 min
before to 10 min after training. The fact that it works when
injected 30 min before training may just mean that it remains
near the site of action for that period. It could be argued that
the drug remains active for 40 min. The important piece of
information is that it ceases to be active when injected at
15 min after training—even though with injection at 10 min
it may remain in the area for another 40 min. This implies
that whatever process is being inhibited by the drug is no
longer susceptible to interference 15 min post-training.
The extent of distribution of a drug in the forebrain
following injection will depend to a large extent on the
lipophilic properties of the drug (see Section 6.1). Because
different antagonists may only have effects at particular
times depending on which stage of memory they influence,
353
there is some uncertainty as to the time at which to deter-
mine the initial dose–response relationship. A pilot study
with a dose estimated from the literature can predict the
time of injection for the dose–response study. As will be
apparent in this review, neurotransmitters can have different
effects at different doses as well as at different times of in-
jection. For studies where memory processing is blocked it
is crucial to determine the minimal dose that will give max-
imum inhibition of memory processes, to avoid possible
unwanted side effects of high doses of drugs. For facilitation
of memory processes it is also important to use the minimal
dose that will give maximum memory enhancement.
2.3.2. Foundation for the chick memory model
Using the protocol of varying the time of injection of
drugs and determining when memory loss first occurs, a
model has been developed of memory formation with very
precise times for the three different stages (all three stages
are seen in the first hour after training).
2.3.2.1. Inhibition of memory processing with strongly rein-
forced training. There are a large number of drugs that are
used to prevent memory formation, but in general they fall
into four categories, based on when and at what stage the
memory disappears after injection. In this review it is not
proposed to make a comprehensive listing of agents affect-
ing memory in the chick but to demonstrate the consistency
of our findings when varying time of injection and time of
test.
LTM: LTM inhibitors, which include the protein synthe-
sis inhibitors cycloheximide and anisomycin, and the PKA
inhibitor lauryl gallate cause memory loss within 60 min
following training (Fig. 3A) Memory does not recover after
the dip at 55 min. These drugs can be injected up to 20 min
post-training but are not effective when given at 25 min
(Fig. 3B).
ITM.B: With drugs that interfere with the latter part of
ITM (ITM.B) memory is retained until 30 min after train-
ing and then lost (Fig. 3C). In conjunction with the data
from memory loss after weakly reinforced training the re-
sults suggest that memory is not consolidated beyond labile
memory, rather than active inhibition of a process. This
interpretation is reinforced by the great variety of drugs
(neurotransmitter antagonists, metabolic inhibitors and ni-
tric oxide synthase inhibitors) that have this effect. Survey
of the times at which these inhibitors become ineffective
in preventing memory reveals two patterns of effect. They
either lose effect around 5 or 10 min or around 20–25 min
after training. Iodoacetate, high doses of noradrenaline and
methoxamine actually inhibit memory at both these times
but not in between (Fig. 3D). Irrespective of the time of
injection memory loss occurs after 30 min.
ITM.A: Drugs that prevent the first part of ITM, i.e. not at
10 min after training but after the 15 min dip (Fig. 3E), are
generally effective given 5 min after training but not 10 min
after training (Fig. 3F). These include drugs that alter
354 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391

Fig. 3. Summary of experiments to illustrate the different stages of memory showing the two different protocols. (A, C, E and G) Chicks were injected
at the same time after training on 100% anthranilate (usually immediately after training) and memory tested (in separate groups of chicks) at specific
times after training. (B, D, F and H) The time of injection was varied around the training trial (0 min) and the retention tested at 120 min after training.
Saline injection represented by open symbols, drug injection by closed symbols. (A and B) LTM inhibitors. (C and D) ITM phase B inhibitors. (E and
F) ITM phase A inhibitors. (G and H) STM inhibitors. The drug studies are the mean of different studies that used a number of different antagonists
to inhibit memory formation. The drugs represented in each graph are detailed as follows. (A and B) LTM inhibitors—protein synthesis inhibitors
cycloheximide injected >5 min after training and anisomycin; non-metabolized amino acid amino-isobutyrate and PKA inhibitor, lauryl gallate. (C and D)
ITM B inhibitors—propranolol, ␤2 -AR antagonist ICI 118,551, serotonin (5 nmol per hem), 5HT antagonist methiothepin; nitric oxide synthase inhibitors
l-NAME, N-arginine, diphenyliodonium (endothelial NOS inhibitor), n-propyl-l-arginine (neuronal NOS inhibitor); metabolic inhibitor iodoacetate,
cycloheximide injected before training. (E and F) ITM.A inhibitors—Na+ /K+ ATPase inhibitors ouabain and ethacrynic acid; metabolic inhibitors,
fluoracetate, fluorocitrate, 2,4-dinitrophenol, methionine sulfoxamine, potassium chloride (40 nmol per hem). (G and F) STM inhibitors: glutamate (40 nmol
per hem) bicuculline, lanthanum chloride, potassium chloride (20 nmol per hem) and l-acetic acid ␤-hydroxamate).
 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
Na+ /K+ ATPase activity such as ouabain and ethacrynic
acid. If a distinction is made between agents that inhibit the
formation of a memory stage and agents that disrupt main-
tenance of that stage the susceptibility to interference of a
memory stage is less than the survival or duration of the
particular stage (Andrew, 1980). Preventing the formation
of a stage leaves the previous stage intact until it decays,
whereas disrupting the maintenance of an existing stage
means that memory is lost straight away. The metabolic in-
hibitor 2,4-dinitrophenol inhibits the expression of ITM.A.
Memory loss occurs immediately after injection of this
inhibitor of oxidative metabolism.
STM: STM inhibitors include drugs that will alter mem-
brane conductance properties such as glutamate (40 nmol
per hem which probably depolarizes membranes) potas-
sium chloride, GABA, lanthanum chloride. When injected
around the time of training these will prevent memory when
first tested 5 min or thereafter (Fig. 3G). These drugs are
not effective in inhibiting memory when given 5 min after
training (Fig. 3H). Controls have demonstrated that this
increase in pecking is specific to the bead used in training
(Gibbs and Ng, 1979b).
There could be problems with the interpretation of
experiments where inhibition of processes produces mem-
ory loss. The drug(s) may just be inhibiting normal cerebral
neuronal function, but this seems unlikely when it can be
seen that there is a pattern of timing of memory loss as well
as a specific pattern of injection times that will produce
memory loss. The conclusion is that these processes are
necessary for the formation of permanent memory, as long
as an interpretation of inability to recall cannot be applied.
2.3.2.2. Enhancement of memory formation using weakly
reinforced training. When chicks are trained using a di-
lute (less aversive) solution of anthranilate on the bead, a
labile memory forms which consists of STM and the first
part of ITM (ITM.A) and lasts only for 30 min. It is possi-
ble to change this memory from one lasting only 30 min to
memory lasting at least 24 h by increasing either the num-
ber of trials or the concentration of anthranilate on the bead
as mentioned above (Crowe et al., 1989a,b). Another way
to consolidate memory is to inject various hormones, and
ACTH, vasopressin and noradrenaline (Crowe et al., 1990)
can all change a labile memory into a permanent one. These
same hormones will change the duration of stages in chicks
given weakly reinforced training in the same manner as they
do for strongly reinforced training (Gibbs et al., 1991).
In the experiments referred to above (Crowe et al., 1990)
the hormones were injected subcutaneously (s.c.) and there
was a limited time over which the hormones were effective
in producing consolidation. When agonists that consoli-
date labile memory are injected directly into the forebrain,
it is generally found that they will have effects as long
as they are injected during the lifetime of labile mem-
ory, i.e. within 25–30 min after weakly reinforced training
(Fig. 4).
355
Fig. 4. Retention levels at 120 min after weakly reinforced training with
20% anthranilate where various agonists were injected at different times
after training. Saline injected chicks (open circles) show no memory
enhancement at any time of injection. The experiments where agonists
have improved memory (closed symbols) show that this is achieved with
injection up to 25 or 30 min after training but not later. The graphs in this
figure come from experiments injecting sodium nitroprusside, the ␣1 -AR
agonist prazosin, serotonin (2.5 nmol per hem), noradrenaline (1 nmol per
hem), the ␤-AR agonist BRL 37,344, arginine vasopressin, glucose and
calcium.
2.3.2.3. Pharmacological specificity rationale. An experi-
mental protocol has been developed to determine the speci-
ficity of a particular receptor agonist for the appropriate
receptor. The action of the agonist is challenged with selec-
tive antagonists or antagonists acting on a range of receptor
subtypes to determine which receptor subtype a neurotrans-
mitter is acting on. This protocol has been used to determine
which receptor subtypes are involved in the action of differ-
ent doses of noradrenaline. Pre-administration of a dose of
a selective receptor antagonist which normally causes am-
nesia should prevent the neurotransmitter having an effect
on memory consolidation. A reduced dose of the antagonist,
which does not interfere with memory processing by itself,
nonetheless should partially occupy the selected receptor and
should shift the dose–response curve to the neurotransmit-
ter in a dose-dependent manner to the right. The same sort
of experiment can be done with receptor agonists to ensure
that the effect of the agonist is on the postulated receptor in
terms of its effect on memory formation. It is apparent from
the experiments to be reported, e.g. the work with ␤-ARs
(Sections 8.2 and 9.2), that our behavioral response protocol
is very sensitive and accurate enough to provide this sort of
data. The actual timing of the challenge can differ depending
on the receptors, neurotransmitters or agonists involved. In
these experiments the two drugs are administered by differ-
ent routes. Preliminary studies may need to be carried out to
determine the appropriate times of injection of the two drugs.
2.3.2.4. Dose–response relationships. To provide a clear
picture of the influence of any drug on memory formation,
it is important to determine the optimum dose to use. In the
situation where memory processing is being inhibited, it is
crucial to find the minimum dose that gives the maximum
356 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391

inhibition of memory processing. If the optimum dose is
not used some of the process being inhibited may be spared
allowing some processing to continue. This argument also
applies to the optimum time of injection (Gibbs and Ng,
1977). Incomplete inhibition or blockade may allow some
processing to continue into the next stage and result in an
incorrect interpretation at to which stage is being affected.
Differences in this respect may occur between drugs that
work on the cell surface, i.e. receptors or on physiological
cell membrane processes tend to provide clear definitions of
stages, whereas drugs that have to get into the cell to block
some biochemical event, e.g. kinase activity are often not as
clear cut in their action and if a little enzymatic activity is
spared this may be enough to partially perform the cellular
function.
It is also apparent from the pharmacological dissection
of memory stages that it is also important to fully inves-
tigate the temporal processing of memory; it is essential

Fig. 5. Injection sites—coronal and sagittal sections of chick brain showing IMHV and LPO injections. Kuenzel et al. ‘A stereotaxic atals of the brain
of the chick (Gallus domesticus)’, pp. 49, 62 and 140, 1988© . Modified and reprinted by permission of the John Hopkins University Press.
 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
to have very accurate timing of injection and training-test
intervals.
2.3.3. Injection procedures
Chicks have a blood–brain barrier (Purdy and Bondy,
1976; Liebner et al., 1997) that is not fully developed at the
time of hatch. However, the effects of noradrenaline may
differ when given by subcutaneous or intracranial injection,
which may be related to its ability to cross the blood–brain
barrier. It is always important to demonstrate that the same
times of injection and test apply to both forms of admin-
istration before using them interchangeably. In addition,
some drugs can have peripheral affects that can affect the
behavioral outcome.
For intracerebral injections, drugs are injected in 5 or
10 ␮l volumes into each hem using a Hamilton repeating
dispenser syringe and a 27-gauge needle. Intermediate hy-
perstriatum ventrale (IMHV) injections are made 2–3 mm
to the left and the right of the midline and 3–5 mm from
the depression at the caudal end of the forebrain at a depth
of 3.0–3.5 mm (Fig. 5). Since the orifice on the needle is
about 0.5 mm, the drug will spread at least 0.5 mm. Smaller
bore needles tend to eject the drug with a greater veloc-
ity than desirable. Injections into the lobus parolfactorius
(LPO) are made 2 mm from the front of the brain and 2 mm
to the left and right of the midline. The needle depth for
these injections is 4.5–5.0 mm, the needle being angled
backwards to reach the target so that it does not penetrate
the hyperstriatum The standard deviation in a group of 20
chicks is generally 0.5–1 mm either side of the intended
target. Control experiments show that memory is the same
in saline injected control chicks, as in untreated chicks.
The injection volume in the chick is greater than those
used in rodents. As well as having an unossified, carti-
laginous skull, the nuclei of the chick forebrain are not as
compact as in mammals. At this age there are large extracel-
lular spaces allowing for distribution of drug with minimal
damage. A pair of chicks is trained within 10 s and injec-
tion also takes the same time. This enables accurate timing
of the procedures necessary for both injection and test ac-
curacy. The use of stereotaxic apparatus is impractical as
it greatly reduces reduce the speed and increases the time
of handling of each chick. The use of the modified head
holder of Davis et al. (1979) is itself stressful. Sandi and
Rose (1994) note that ‘chicks could not be injected earlier
than 5 min after training without the injection procedure
itself resulting in amnesia’.
Although the distribution of injected drug can be quite
extensive (Davis et al., 1979), its diffusion will depend on
whether the drug is lipophilic and whether the injection site
allows access of the drug to the ventricles. In addition, pro-
vided the minimum dose is used that will produce amnesia,
the effective concentration will only be at the site of injec-
tion, and further away the dose will become less effective.
This was demonstrated when 14 C-leucine incorporation
into protein was only inhibited in the hem receiving an
357
injection of a protein synthesis inhibitor, not the untreated
hem (Gibbs et al., 1979). The action of an injected drug can
be restricted to the side of injection. In addition, there is
now considerable evidence that unilateral injection of drug
may produce actions that are dependent on the hem into
which it is injected (Zhao et al., 1994; Gibbs et al., 2002).
In an experiment in which a head holder was used (Gibbs
and Ng, unpublished observations) we found that the depth
of injection was critical (Fig. 6). The STM inhibitor, potas-
sium chloride (100 nmol per hem, 10 ␮l of 2 mM KCl), the
ITM inhibitor ouabain and the LTM inhibitor anisomycin
were injected 5 min before training at depths of 2.5, 3.5 and
4.5 mm. Only the injections at 3.5 mm produced significant
amnesia.
3. Anatomy of the chick brain with
respect to memory studies
When this work started in the late 1960s there was
very little information available about the structure of the
chick brain. More detailed information is now available
on the functional anatomy of the chick brain and the rela-
tionship of various structures to those in the mammalian
brain.
Structurally the avian brain appears very different to the
mammalian brain. There was a divergence in evolutionary
development with the neocortex becoming internalized in
birds; whereas in mammals the neocortex expanded out-
wards (Romer, 1977). With the increase in knowledge of
structure and function of the avian forebrain, it is becoming
apparent that the bird brain has all the components that
are present in the mammalian brain, they are just arranged
differently and “large areas of the avian telencephalon
can be considered equivalent to the mammalian neocortex”
(Dubbeldam, 1991) (Table 1). The avian forebrain has
ceased to be considered to be all basal ganglia (Table 1).
The important regions for the current review are the
dorsoventricular ridge comprising the hyperstriatum ven-
trale and the neostriatum, which are considered to be the
equivalent of the association cortex, and the basal ganglia—
caudate-putamen being the LPO. The hippocampus in birds
is considered functionally homologous to the mammalian
hippocampus, despite differences in cellular structure
(Bolhuis and MacPhail, 2001). A recent review (Colombo
and Broadbent, 2000) compares results obtained from hip-
pocampal lesions in birds and mammals and concludes that
they have essentially the same function in both classes.
“Despite 300 million years of independent evolution, there
are no degrees of freedom in the evolution of hippocampal
function.” Both birds and mammals with damage to the
hippocampus are severely impaired on a variety of spatial
tasks, but not impaired on a variety of visual tasks including
visual discrimination. The hippocampus in both birds and
mammals is important for the processing and retention of
spatial rather than purely visual information.
358 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391

Fig. 6. Effect of KCl, ouabain and anisomycin injected 5 min before training at different depths into the brain targeting hyperstriatum accessorium,
hyperstriatum ventrale and paleostriatum. Chicks were tested 60 min (A) or 120 min after training (B and C). Only injections into IMHV produced
memory loss. Injections of 10 mM KCl or ouabain at +10 min had no effect (∗ P < 0.05, unpublished observations). Repeat groups of ouabain and
anisomycin injected chicks are included in (B and C).

Table 1
Suggested functional homologies between bird and mammalian brains. Adapted from Dubbledam (1991)
Mammals Birds Abbreviation

Visual cortex Wulst, hyperstriatum accessorium, hyperstriatum dorsale HA, HD

Association cortex Dorsoventricular ridge: hyperstriatum ventrale, neostriatum, ectostriatum HV, N, E, Bas, A
nucleus basalis, rostral archistriatum
Prefrontal cortex Lateral neostriatum LN
Hippocampus Hippocampus H
Amygdala Archistriatum, medial and caudal A
Caudate Putamen, basal ganglia Lobus parolfactorius, paleostriatum augmentatum LPO, PA
Globus pallidus extint Paleostriatum primitivum nucleus intrapeduncularis PP, INP
 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391 359

3.1. Function of brain areas implicated in
memory storage in the chick
The original studies investigating areas of the forebrain
recruited during memory in passive avoidance learning in
chicks (Kossut and Rose, 1984) used the 2-deoxyglucose
autoradiographic technique of Sokoloff (1981) to measure
glucose utilization as a consequence of learning. Enhanced
glucose utilization is likely to occur with increased neu-
ronal activity, whether because of increased firing rate or
metabolic mobilization. Chicks were trained with either
water or anthranilate and the overall pattern of labeling was
similar in both groups. However, quantitative densitometric
analysis showed significant increases in the intensity of la-
beling of three regions—LPO (11%), IMHV (10%) and the
paleostriatum augmentatum (PA) (13%). Interestingly, there
were differences between the left and the right hems (Rose
and Csillag, 1985). With administration of 2DG into the
IMHV at −5, +10 and +30 min there was greater incor-
poration in the left than the right IMHV, the only increase
in the right was with injection at 10 min after training. This
has important bearing on the lateralization of memory pro-
cesses in the chick, where the left hem is predominant in
memory storage (Gibbs et al., 2002). There was an increase
in uptake of 2DG in the left LPO when the 2DG was in-
jected at the two earlier times, with no differences above
controls in the right LPO at any of the injection times.
In many studies since this time Stewart and co-workers
(e.g. Stewart and Rusakov, 1995; Rose and Stewart, 1999)
have examined the nature of the alterations in the circuitry
at the neuronal and synaptic level at different times af-
ter memory formation. Within the first hour of training
there are increases in synaptic density in the IMHV that
are largely transient, but in the LPO, bilateral changes in
synaptic density are still present at 24 h post-training. A
pretraining intracranial (IMHV) injection of anisomycin,
which results in amnesia, reduced the bilateral increases
in synaptic density (of spine and shaft synapses) seen in
saline injected trained controls, demonstrating that protein
synthesis de novo is involved in the post-training increase
in synaptic density in the LPO.
There are many excellent reviews on chick brain anatomy
(e.g. Reiner et al., 1984; Dubbeldam, 1991; Csillag et al.,
1994; Szekely et al., 1994; Csillag, 1999; Durstewitz et al.,
1999; Szekely, 1999; Deng and Rogers, 2000; Medina and
Reiner, 2000) and no attempt will be made to give a compre-
hensive review of avian forebrain anatomy, instead a brief
account of areas and pathways of pertinence to this review
follows, starting with visual and sensory input (Fig. 7).
There are two major visual projections in the avian
brain—the thalamofugal pathway innervates the visual
Wulst via a direct thalamic relay and the tectofugal pathway
passes via the optic tectum to the ectostriatum (Fig. 8).
A primary visual area and a primary somatosensory–
somatomotor area are present in the avian Wulst, likely to
be homologous to their counterparts in mammals. Medina
and Reiner (2000) conclude that similar physiological and
structural traits such as lamination and binocularity in the
Wulst and the mammalian neocortex appear to have evolved
independently in birds and mammals.
There are other somatosensory areas in the rostral extent
of the Wulst, and also within the nucleus basalis. The nucleus
basalis, situated rostral to the LPO, mainly processes trigem-
inal information but also receives additional somatosensory
and auditory input. The secondary sensory areas for all
modalities are reciprocally connected with a region in the

Fig. 7. Sagittal section of 1.4 mm from midline showing details of relevant brain structures. Kuenzel et al. ‘A stereotaxic atals of the brain of the chick
(Gallus domesticus)’, pp. 49, 62 and 140, 1988© . Modified and reprinted by permission of the John Hopkins University Press. N.B.: positions of lobus
parolfactorius (LPO), locus coeruleus (LoC), hyperstriatum ventrale (HV), neostriatum (N), hippocampus (Hp), hyperstriatum accessorium (HA).
360 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
Fig. 8. Diagrammatic representation in sagittal section of visual pathways
in avian brain (adapted from Shimuzu, 1999).
dorsocaudal neostriatum, which has been suggested to be the
homologue of the mammalian prefrontal cortex (Hartmann
and Gunturkun, 1998; Braun et al., 1999). Other multimodal
areas probably exist in the IMHV and the intermediate
neostriatum. At the next level of information processing in
the avian brain, sensory information is funneled in parallel
from both the tertiary as well as the secondary sensory
areas to the basal ganglia and in addition to the ventrolat-
erally located archistriatum. The avian archistriatum has
been divided functionally into the somatic sensorimotor and
a viserolimbic division considered to be equivalent to the
mammalian amygdala.
The connectivity, neurotransmitter content, and cytoar-
chitecture of the avian basal ganglia are very similar to that
in mammals. A functional segregation of the avian stria-
tum into associative, sensorimotor and limbic territories,
based on the palliostriatal connections, has been suggested
(Veenman et al., 1995). The PA and LPO make up the
dorsal (somatomotor) striatum. Ventral striatal structures
include the nucleus accumbens (Acc), the bed of the stria
terminalis (BNST) and the olfactory tubercule (TO), which
constitute the ‘visceral-limbic’ parts of the avian striatum.
The pallidal parts of the avian basal ganglia consist of the
paleostriatum primitivum (PP), which is homologous to the
globus pallidus of mammals, and the ventral pallidum (VP),
which is comparable to the ‘limbic’ VP of mammals. The
striatum consists of many of the same neuronal constituents
in birds and mammals (Reiner et al., 1984). The avian LoC
lies ventrally to the cerebellum in the hindbrain.
The hippocampus in the bird is considered to be a func-
tional homologue of the mammalian hippocampus, and is
important for spatial learning (e.g. Shettleworth, 1990).
However, like the mammalian hippocampus it appears not
to be very important for processing and retention of purely
visual information (Szekely, 1999; Colombo and Broadbent,
2000).
The main areas of interest for the current work are the
hyperstriatum ventrale and the LPO, although because of
the proximity of other areas around them such as the neos-
triatum and the nucleus basalis respectively, influences of
injected drugs in the surrounding areas cannot be ruled
out. There are numerous studies showing the importance
of IMHV and LPO in the formation of memories for the
single-trial passive avoidance task in chicks (Gilbert et al.,
1991; Patterson and Rose, 1992; Stewart et al., 1996; Sandi
and Rose, 1997; Csillag, 1999; Rose, 2000).
The archistriatum receives afferent input from the IMHV
and projects to the LPO (Csillag et al., 1994; Csillag, 1999).
Although there is functional evidence to suggest that the
IMHV and LPO are connected, there is no anatomical ev-
idence for a direct connection between the two structures.
The connection between IMHV and LPO is via the archis-
triatum (Csillag, 1999). Anterograde connections from
LPO to hyperstriatum, neostriatum, paleostriatum in the
forebrain, and to various midbrain regions, including the
substantia nigra and the LoC have been shown. LPO effer-
ents are coextensive with tyrosine hydroxylase-positive cells
in the substantia nigra, LoC and other regions of the mes-
encephalic and pontine tegmentum. Retrograde connections
were seen from the LoC, the substantia nigra, archistria-
tum to the LPO but none from the hyperstriatum ventrale
(Szekely et al., 1994). The reciprocal connections between
the LoC and the LPO suggest that the LPO is likely to par-
ticipate also in the mediation of ascending noradrenergic
input.
Like the mammalian caudate putamen, the LPO seems to
have an extremely high concentration of a number of neu-
rotransmitters, e.g. dopamine (Metzger et al., 1996; Stewart
et al., 1996), GABA (Csillag et al., 1987) acetylcholine
(Mezey et al., 1999). Changes in synaptic morphology,
receptor binding and 2DG metabolism have been demon-
strated in the LPO of the domestic chick after passive
avoidance training (Stewart et al., 1992; Hunter and Stewart,
1993; Lowndes and Stewart, 1994; Stewart and Rusakov,
1995). Experimentally induced stress and passive avoid-
ance training leads to an increase of extracellular glutamate
and dopamine in the LPO (Gruss and Braun, 1997; Daisley
et al., 1998). The nigrostriatal and basal ganglia in general
play similar roles in the initiation and control of movement
in birds and mammals (Reiner and Anderson, 1990; Reiner
et al., 1994).
3.2. Distribution of noradrenergic fibers and
cell bodies in avian brain
The overall distribution of catecholaminergic cell bodies
in birds closely resembles that in mammals. Whilst the
catecholaminergic cell groups of the avian retina, forebrain
and midbrain appear to be predominantly dopaminergic,
the catecholaminergic groups of the hindbrain are typically
noradrenergic or adrenergic. The forebrain of the bird is
extremely rich in dopaminergic fibers and relatively sparser
in noradrenergic fibers (Reiner et al., 1994).
The noradrenergic neurons of the LoC have widespread
projections to all levels of the avian CNS and account for
most of the noradrenergic fibers (Kitt and Brauth, 1986).
 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391 361

3.3. Distribution of adrenoceptor subtypes in avian brain 4.1. The effect of intracranial injection of noradrenaline

Based on work in chicks, ␣1 -, ␣2 - and ␤-ARs all appear
to be present in birds and display binding characteristics
similar to those in mammals (Dermon and Kouvelas, 1988;
Reiner et al., 1994). The binding affinity of ␣1 -ARs is
slightly higher in birds than in mammals, but the number
of sites is lower than in mammals, which is consistent with
the fact that the amount of noradrenaline and adrenaline is
higher in the avian brain than in mammals (Balthazart et al.,
1989). ␣2 -ARs are heterogeneously distributed throughout
the avian brain (Ball et al., 1989) and it has been suggested
that most of the ␣2 -ARs are located at the post-synaptic
level (Balthazart and Ball, 1989). The three receptor types
show some individual differences in their distribution, but all
tend to be found in regions that contain noradrenergic fibers
(Reiner et al., 1994). The ␤1 - and ␤2 -ARs have been found in
the chick brain; however, the distribution of ␤1 -ARs seems
relatively sparse, limited to the hyperstriatum ventrale and
cerebellum. ␤2 -ARs show a wider distribution throughout
the brain (Fernandez-Lopez et al., 1997; Revilla et al., 1998).
Differences in reports regarding distribution of the ARs may
be due to the different ligands used for the binding studies.
4. Identification of the AR subtypes responsible
for the action of noradrenaline on memory
consolidation in the chick
When noradrenaline is released in the brain and sub-
sequently modulates memory consolidation, there is the
potential for action at any of the AR subtypes and in a num-
ber of different areas in the brain. The question becomes—
how can noradrenaline have any selectivity in its action?
Increases in the levels of noradrenaline in plasma, as a
consequence of stress, have been implicated in the mod-
ulation of memory storage. Noradrenaline release occurs
in learning situations with a positive reinforcer as well as
those where the reinforcer is negative. There is evidence
that levels of noradrenaline in the brain increase with train-
ing (spontaneous alternation, Men et al., 1999; emotionally
arousing and spatial memory tasks, Clayton and Williams,
2000) and stress (escapable and inescapable footshock,
Quirarte et al., 1998; Williams et al., 1998). If the increase
in noradrenaline levels in the brain is mimicked by injection
of noradrenaline into the IMHV of the chick forebrain after
weakly reinforced training, memory processing is immedi-
ately reinstated. When saline is injected immediately after
training, memory is lost after 30 min and there is no consol-
idation of the labile memory (Fig. 9B). When noradrenaline
(1 nmol per hem) is injected into the IMHV immediately
after training, memory levels are as good at 120 min as after
training with strongly reinforced training (Fig. 2B). There
is a significant difference in the pattern of memory retention
seen in weakly and strongly reinforced training; the time
of the temporary losses in retention has shifted from 15 to
25 min (Fig. 2B and 9B) and from 55 to 90 min after train-
ing. The duration of STM increased by 10 min and ITM by
35 min, suggesting that this dose of noradrenaline has an
effect on both stages of memory processing.
Noradrenaline can be injected up until 30 min after weakly
reinforced training to consolidate the labile memory; but
when injected 40 min or later, it fails to have any effect
on disc. ratios on the 120 min test (Fig. 9A). Therefore,
noradrenaline can only consolidate or reinstate the memory
whilst the labile memory is present.

Fig. 9. Enhancement of weakly reinforced learning by noradrenaline (1 nmol per hem). (A) Noradrenaline injected into the IMHV of separate groups
of chicks at different times after training was only effective in enhancing consolidation (measured 120 min after training) when the injection is given
during the lifetime of labile memory, i.e. up to 30 min after training. Saline injection at any of these times does not enhance consolidation. (B) Retention
in separate groups of chicks tested at times between 5 and 100 min after training with noradrenaline injected immediately after training (unpublished
observations). The time course of memory retention seen after saline injection shows decay of memory commencing 35 min after training, with virtually
no memory left after 60 min.
362 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
4.2. Modification of action of noradrenaline on memory
consolidation in the IMHV by different AR subtype
antagonists
The action of noradrenaline could be at any one or any
combination of the nine different AR subtypes. To determine
which of the AR subtypes could be involved, a series of
experiments were conducted challenging the dose–response
relationship to noradrenaline with selective AR antagonists
to the different ARs. Noradrenaline injected at 20 min after
weakly reinforced training would normally consolidate la-
bile memory. Selective antagonists or saline were injected
s.c. 5 min after the training trial and noradrenaline was
injected intracerebrally 15 min later. The selective antago-
nists used were—prazosin (␣1 -AR); yohimbine (␣2 -AR);
propranolol (␤1+2 -ARs) and SR 59230A (␤3 -AR).
Dose–response studies for the different antagonists also
allowed the determination of the minimal dose that inhib-
ited memory from strongly reinforced training (the data
is shown in Figs. 19, 24A, 30, 37 for each antagonist).
The time of injection of antagonist (relative to that of the
agonist) necessary to challenge the action of the agonist
was also determined by keeping the agonist injection time
constant and varying the time of injection of the antagonist.
For example, if the agonist was given 20 min after training,
the time of the antagonist injections were 5, 10 or 15 min
after training. The design of the experiments challenging
the action of noradrenaline is illustrated in Fig. 10.
The dose–response relationship for noradrenaline in-
jected into the IMHV at +20 min after weakly reinforced
training (with saline injected 5 min after training) was bell
shaped. Doses of 0.1, 0.3 and 1.0 nmol per hem significantly
enhanced the consolidation of the labile memory (Fig. 11),
whereas higher doses of noradrenaline (3.0 and 10.0 nmol
per hem) did not promote consolidation. It cannot be seen
Fig. 10. Experimental protocol showing the selection of times for antago-
nist challenges to agonist enhancement of memory with weakly reinforced
training. The selective antagonists or saline were injected s.c. 5 min after
training, and different doses of the agonist (noradrenaline) injected i.c.
20 min after training. Retention was tested 120 min after training.
Fig. 11. Dose–response relationship at 120 min for noradrenaline injected
20 min after weakly reinforced training. Results from two different ex-
periments (from Gibbs and Summers, 2000).
from weakly reinforced training data whether there is an
action of the higher doses on memory processing or in fact
whether the high doses could inhibit memory formation.
Subsequent experiments (Fig. 14) showed that memory
consolidation is prevented by the high doses of nora-
drenaline.
The results shown here (Fig. 11) are from two separate
experiments, and illustrate one of the problems that can
arise with weakly reinforced training. The problem is one
of unstable baseline responses shown here with the lower
doses of noradrenaline. In one experiment injection of the
low doses of noradrenaline (0.003 and 0.01 nmol per hem)
resulted in a slightly higher discrimination score than the
other. This may have been due to the base line levels of
noradrenaline in vivo being higher on this day than in the
other experiment. Whether this was due to conditions on
the day, e.g. excessive temperatures, noise in the laboratory,
something that occurred at the hatchery, or in transit is un-
known; but it emphasizes the importance of having quiet
controlled conditions for these experiments.
The ␤3 -AR selective antagonist SR 59230A (30 pmol
per chick, ∼750 pmol/kg) only prevented the action of no-
radrenaline at 0.1 nmol per hem (Fig. 12A). At the higher
dose of 3.0 nmol per hem there was a tendency for SR
59230A to prevent the inhibition produced by noradrenaline.
Whether this shift represents competition by noradrenaline
for sites occupied by SR 59230A or whether it reflects the
dose–response curve for noradrenaline acting at ␤2 -ARs is
unclear. This represents one of the problems of injecting
a neurotransmitter with actions at multiple receptor sites.
Noradrenaline (0.1 nmol per hem) promoted consolidation
and this effect was absent following blockade of ␤3 -ARs.
It is concluded that noradrenaline at this dose level acts on
␤3 -ARs to enhance memory consolidation.
When ␤2 -ARs are inhibited by propranolol, a higher
dose of noradrenaline (1.0 nmol per hem) fails to promote
memory consolidation (Fig. 12B). There was no difference
 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391 363

Fig. 12. Dose–response relationship at 120 min for noradrenaline challenged by prior injection of selective AR antagonists. There are two curves for
saline represented in (A–D). (A–E) Noradrenaline injected into IMHV 20 min after weakly reinforced training. (F) Noradrenaline injected into LPO
20 min after training. The selective antagonists were injected s.c. 5 min after weakly reinforced training. The selective antagonists were SR 59230A for
␤3 -ARs (A); propranolol for ␤1 -/␤2 -ARs (B); prazosin for ␣1 -AR (C); both S 59230A and propranolol were injected together in (D) and yohimbine for
␣2 -AR (E and F). These were effective in challenging different doses of noradrenaline. (A–D) from Gibbs and Summers, 2000; (E) and (F) from Gibbs
and Summers, 2002.
364 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
with any other doses between saline and propranolol
pre-administration. This result suggests that doses of no-
radrenaline of between 0.3 and 3.0 nmol per hem promote
memory consolidation via an action on ␤2 -ARs. An action
of noradrenaline at ␤1 -ARs is unlikely as manipulation
during ITM of this AR subtype does not influence memory;
hence they appear to have no role in memory consolidation.
However, they may play a role in STM. The effect of the
higher doses of noradrenaline (3–10 nmol per hem) may
result from an action on ␣1 -ARs since the ␣1 -AR antago-
nist prazosin (1 nmol per chick ∼25 nmol/kg) successfully
prevented the inhibition of memory formation (Fig. 12C).
When both ␤2 - and ␤3 -ARs were blocked (Fig. 12D), only
the effects of 0.1 and 0.3 nmol of noradrenaline per hem were
different from control groups. It may have been expected
that the effects of 1.0 nmol of noradrenaline per hem would
be prevented by combined blockade of ␤2 - and ␤3 -ARs.
This dose of noradrenaline may be high enough to over-
come the blockade by propranolol and SR 59230A. It was
evident (Fig. 12A and B) that in the presence of SR 59230A
the noradrenaline dose–response curve for ␣1 -AR mediated
effects on memory were shifted to the right whereas in the
presence of propranolol it was shifted to the left. In the pres-
ence of both antagonists the ␣1 -AR mediated effects were
similar to controls.
Injection of the ␣2 -antagonist yohimbine (30 pmol per
chick, ∼750 pmol/kg) failed to prevent memory consolida-
tion when noradrenaline was injected into IMHV (Fig. 12E).
In this instance, the antagonist was administered 10 min
post-training, as preliminary data showed that this was
the most effective time of administration for yohimbine
to inhibit memory consolidation (Fig. 25A). This result
was surprising as it is recognized that yohimbine inhibits
memory formation and clonidine and oxymetazoline, two
selective ␣2 -AR agonists promote memory consolidation,
yet there was no effect on the memory enhancing effect of
noradrenaline injected into the IMHV.
4.3. α 2 -Adrenoceptor involvement in the action of
noradrenaline in LPO
For various reasons (see Section 6) it was suspected that
another brain region might be involved in the action of
␣2 -AR agonists and antagonists on memory formation. The
region chosen for investigation was the LPO, which has been
shown to play a role in memory formation (Kossut and Rose,
1984; Serrano et al., 1992).
Noradrenaline injected into the LPO produced a very simi-
lar dose–response relationship to noradrenaline injected into
the IMHV (Fig. 12F). Increasing the dose of noradrenaline
from 0.1 pmol per hem to 1.0 nmol per hem produced in-
creasingly higher levels of memory retention. The highest
dose 10 nmol per hem, like when injected into the IMHV,
was not effective in promoting memory consolidation.
Subcutaneous injection of yohimbine 10 min after weakly
reinforced training inhibited the action of noradrenaline in
the LPO injected 10 min later in a dose dependent manner
(Gibbs and Summers, 2002).
4.4. Action of a selective β-adrenoceptor
agonist—isoprenaline
The action of different doses of noradrenaline on ␤2 -
and ␤3 -ARs was confirmed in a series of studies using the
␤-AR agonist isoprenaline to promote memory consolida-
tion. Isoprenaline is a selective ␤-AR agonist, which acts
at all three ␤-ARs, but has very little effect on ␣-ARs.
Isoprenaline injected into the IMHV at 20 min after
weakly reinforced training promoted the consolidation of
memory in a dose dependent manner (Fig. 13A). Isopre-
naline has a higher affinity for ␤3 -ARs than noradrenaline
and promoted memory consolidation at a lower dose
(0.03 nmol per hem). Isoprenaline can be injected 10 or
20 min after training with the same result. Injection of
saline at 5 min after training had no effect on the dose–
response relationship at either time of injection. When the
dose–response relationship for isoprenaline was challenged
with SR 59230A (30 pmol per chick), isoprenaline was in-
effective in enhancing memory consolidation at 0.03 nmol
per hem (Fig. 13B). The ␤1+2 -AR antagonist propranolol
(100 nmol per chick) prevents the effect of the higher doses
(1.0–10 nmol per hem) (Fig. 13C). When both antagonists
were injected together they blocked all effects of isopre-
naline in enhancing consolidation (Fig. 13D).
4.5. Inhibition of memory consolidation by
high doses of noradrenaline
Intracerebral injection of noradrenaline (10 nmol per hem)
immediately after strongly reinforced training (Fig. 14A)
produced loss of memory 120 min after training. Memory
levels were the same as saline injected controls until 30 min
after training, but at 40 min memory was gone. Nora-
drenaline could be injected at any time between 5 min before
training and 5 min after training and prevented memory con-
solidation (Fig. 14B). Interestingly, when injected 25 min
after training noradrenaline prevented consolidation. Injec-
tions given 10–20 min after training and at 30–35 min after
training did not affect memory retention. This result implies
that the high dose of noradrenaline has selective effects on
memory processing on a part of the cascade of physiologi-
cal events underlying the early stages of memory formation.
The effect of high doses of noradrenaline is compared to the
action of the ␣1 -AR agonist—methoxamine in Section 5.
4.6. Conclusion
Noradrenaline has actions on memory formation by
acting at both ␣- and ␤-ARs (Fig. 15). These experiments
demonstrate that in addition to noradrenaline exerting se-
lectivity via AR subtypes, there is also selectivity caused
 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391 365

Fig. 13. Facilitation of consolidation of weakly reinforced memory by the ␤-AR agonist isoprenaline injected at 10 or 20 min after training with saline
injected 5 min after training in four of the experiments (A). When isoprenaline was challenged by the selective ␤3 -AR antagonist SR 59230A, the ability
of low doses isoprenaline to consolidate injected 10 or 20 min after training were reduced (B); the action of higher doses of isoprenaline were reduced
by the ␤1+2 AR antagonist propranolol (C). When both SR 59230A and propranolol were injected 5 min after training, isoprenaline 20 min after training
was unable to enhance consolidation (D) (20 min data from Gibbs and Summers, 2000).

Fig. 14. Inhibition of strongly reinforced training by high doses of noradrenaline (10 nmol per hem). Injected immediately after training noradrenaline
causes memory loss 30 min later (A). With injections from 5 min before to 5 min after training chicks were amnestic on test 120 min after training.
Injection 25 min after training also resulted in memory loss (B) (Gibbs and Summers, 2001b).
366 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
Fig. 15. Summary of AR involvement in enhancement of consolidation
of weakly reinforced memory by noradrenaline injected into the IMHV
20 min after training. The 0.1 nmol noradrenaline per hem is acting via
␤3 -ARs; 1 nmol per hem via ␤2 -ARs and 3–10 nmol per hem via ␣1 -ARs.
The action via ␣1 -ARs is only seen as no memory consolidation with
weakly reinforced training, other studies employing strongly reinforced
training show that it is preventing consolidation.
by an action in different locations within the brain. This
situation occurs when noradrenaline is released within the
forebrain from neurones controlled by the LoC and perhaps
by other brain stem nuclei.
When a labile memory is formed, low doses of nora-
drenaline (0.1 nmol per hem) injected into the IMHV en-
hance memory consolidation by activation of ␤3 -ARs. As
the dose of noradrenaline is increased to 1.0 nmol per hem,
labile memory is consolidated predominantly via an action
on ␤2 -ARs. Still higher doses of noradrenaline (10 nmol
per hem) are inhibitory and act via ␣1 -ARs. High doses
of noradrenaline prevent the consolidation of the memory
trace at 30 min after strongly reinforced training. These re-
sults suggest that as the amount of noradrenaline released
by a stimulus increases, it will act firstly at ␤3 -ARs, then at
␤2 -ARs, to increase memory consolidation but at high levels
of stimulation there is inhibition of memory consolidation
by activation of ␣1 -ARs.
5. ␣1 -Adrenoceptors
␣1 -ARs are clearly involved in the action of high doses
of noradrenaline (10 nmol per hem) to inhibit memory
consolidation. The evidence includes competitive blockade
of the response by prior administration of the selective
␣1 -AR antagonist prazosin (Fig. 12D) and absence of an in-
hibitory effect with the selective ␤-AR agonist, isoprenaline
(Fig. 13A), which lacks activity at ␣1 -ARs. This effect is
characterized by a lack of memory consolidation (Fig. 14).
Labile memory, which normally lasts for 30 min, is therefore
still intact, but memory processing does not pass beyond the
Fig. 16. Dose–response curve at 120 min after training for the ␣1 -AR
agonist methoxamine for chicks trained on 100% anthranilate. Methox-
amine was injected into IMHV 20 min after training (from Gibbs and
Summers, 2001b).
trigger occurring at 30 min. The high dose of noradrenaline
therefore appears to prevent further processing.
The effects of noradrenaline are complex and it was pos-
tulated that high doses of noradrenaline should also have
effects on other ARs (␤2 - and ␤3 -ARs which are facilita-
tory). For this reason it was decided to examine the effects
of a drug that selectively stimulated ␣1 -ARs.
5.1. Inhibition of memory for strongly reinforced
learning by α 1 -adrenoceptor agonists
The specific ␣1 -AR agonist, methoxamine, when injected
into the IMHV 20 min after strongly reinforced training, pro-
duced a dose dependent inhibition of memory consolidation
(Fig. 16). Complete prevention of consolidation occurred
with 1.0 nmol per hem. However, when injected s.c.,
methoxamine failed to produce inhibition of memory forma-
tion. Since methoxamine is a vasoconstrictor, subcutaneous
injection may result in slow absorption into the circulation
and a lack of effective concentrations reaching the brain.
As with noradrenaline, the ␣1 -AR agonist inhibited mem-
ory formation (Fig. 17B) when given 5 and around 20 min
after training. The two different time periods when memory
is susceptible suggests a highly specific action on particu-
lar stages of memory formation. The more limited time of
vulnerability to methoxamine is possibly due to endogenous
release of noradrenaline acting on other AR subtypes.
Memory consolidation does not occur in the presence of
methoxamine (Fig. 17A) and memory formation does not
progress beyond 30 min.
5.2. Specificity of action of α 1 -adrenoceptor agonists
The specificity of action of methoxamine was challenged
by subcutaneous injection of the ␣1 -AR antagonist prazosin
(0.1 nmol per chick) 5 min after training. The dose–response
relationship for methoxamine was shifted to the right in a
parallel manner with a dose of prazosin that would promote
consolidation of weakly reinforced learning, but the time of
 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
Fig. 17. Prevention of consolidation of strongly reinforced memory by ␣1 -AR agonist methoxamine. Injection into IMHV at 5 or 20 min after training
resulted in memory loss on tests after 30 min (A). When tested 120 min after training, methoxamine was most amnestic injected at 5 and 20 min (B)
(Gibbs and Summers, 2001b).
injection of the antagonist was not optimal for producing
the challenge.
To determine the correct time at which to inject prazosin,
a study was carried out where a non-facilitatory dose of
prazosin (30 pmol per chick) was injected 5–15 min before
the methoxamine, i.e. 5–15 min after training (Fig. 18A).
This lower dose of prazosin was effective in challenging
only when given 5 min before the methoxamine.
Using this timing, the dose–response curve for methox-
amine was challenged with prazosin (Fig. 18B), i.e. prazosin
was injected s.c. 5 min before methoxamine and successfully
challenged the methoxamine-induced inhibition of mem-
ory. If the action of methoxamine on memory formation is
due to its specific action at the ␣1 -AR then occupation of
the receptors by prazosin should decrease its potency. To
show that this effect of prazosin was specific to the action
of methoxamine on ␣1 -ARs, the action of methoxamine
was compared with the vasoconstrictor endothelin-1, which
also inhibits memory consolidation (Gibbs and Summers,
2001b). In contrast to the result with methoxamine, pra-
zosin failed to shift the dose–response curve to endothelin-1
(Fig. 18C).
5.3. Consolidation of labile, weakly reinforced,
memory by α 1 -adrenoceptor antagonists
Both subcutaneous (+5 min post-training) and intracere-
bral (+0 min) administration of prazosin enhanced memory
consolidation in a dose-dependent manner in chicks given
weakly reinforced training. Intracerebral administration was
more effective at lower doses than subcutaneous adminis-
tration (Fig. 19).
Memory consolidation was enhanced by intracerebral ad-
ministration of prazosin (0.1 nmol per hem) at two different
time periods—0–5 min after training and 20–25 min after
training (Fig. 20B). Interestingly, a comparison of methox-
amine (Fig. 17B) with prazosin shows a similar pattern in
367
terms of when the agonist and the antagonist have an effect
on memory consolidation. Both drugs have an effect on
memory given 5 and 20 min after training.
Prazosin did not enhance memory when injected 5 min
before training; in fact, when given to chicks prior to strongly
reinforced learning, it produced memory impairment. The
results shown in Figs. 17B and 20B suggest that there are
two periods after training which correlate roughly with STM
and the time of consolidation into permanent memory. The
time of test following injection immediately after weakly
reinforced training reveals an extension of STM, with the
dip in retention shifting from 15 to 25 min but no change in
the duration of ITM (Fig. 20A). The second dip occurring at
65 min, still only 10 min later than normally seen after full
strength anthranilate training.
5.4. Conclusion
Selective stimulation of ␣1 -ARs produced effects similar
to those with high doses of noradrenaline suggesting that
noradrenaline acts in the IMHV via ␣1 -ARs. ␣1 -AR mRNA
is widely expressed in rat brain, both in the cerebral cortex
and in the hippocampus (Nicholas et al., 1996).
There are a number of candidates as to how stimulation
of ␣1 -ARs affects memory formation. ␣1 -ARs are found
on a wide variety of cell types in the CNS: neurones,
dendrites and nerve terminals, astrocytes, smooth muscle
and endothelial cells of the cerebral vasculature (Cohen
et al., 1997). In the peripheral nervous system activation of
␣1 -ARs causes vasoconstriction, with vascular tone being
largely determined by the balance between ␣- and ␤2 -ARs
on blood vessels. In brain noradrenaline is considered to be
a weak vasoconstrictor, so it may be considered unlikely to
be the mode of action of the ␣1 -AR agonist. However, the
powerful vasoconstrictor, endothelin 1, does cause memory
loss when injected into the brain, which is not challenged by
prior administration of the ␣1 -AR antagonist prazosin. The
368 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
Fig. 18. Challenge of the inhibitory effect of methoxamine on strongly re-
inforced learning. A non-enhancing dose of the ␣1 -AR antagonist prazosin
only challenged methoxamine when injected 5 min beforehand (15 min
after training). Injections at 5 or 10 min after training did not chal-
lenge the amnestic effect of methoxamine (A). Pre-administration of pra-
zosin (s.c.) 5 min before methoxamine (IMHV) shifted the methoxamine
dose–response curve to the right, making methoxamine less effective in
preventing memory consolidation (B). This dose of prazosin did not shift
the dose–response to endothelin (C) (Gibbs and Summers, 2001b).
exact mechanism of action of vasoconstrictors in memory
loss has yet to be determined.
Another possibility for ␣1 -AR mediated memory loss is
the induction of glutamate release, which is known to cause
memory inhibition (Gibbs and Ng, 1979b). If the role of no-
radrenaline in enhancing neuronal information processing
is to increase the signal-to-noise ratio (Waterhouse et al.,
1988; Buzsaki, 1989), high levels of noradrenaline acting
at ␣1 -ARs, would be expected to increase glutamate release
Fig. 19. Prazosin enhancement of weakly reinforced learning tested at
120 min. Prazosin was given by intracranial or subcutaneous injection
immediately (i.c.) or 5 min (s.c.) after weakly reinforced training. (Gibbs
and Summers, in press).
and cause an increase in excitatory post-synaptic currents
(Marek and Aghajanian, 1999). This increase in glutamate
would increase the background noise and could decrease
the signal-noise-ratio leading to a loss of information. Nora-
drenaline, acting via ␣1 -ARs, is known to facilitate cortical
neuronal responses to glutamate (and glutamatergic synaptic
inputs) with both iontophoretic application and activation
of the coeruleocortical pathway (Mouradian et al., 1991;
Devilbiss and Waterhouse, 2000)). The glutamate levels need
only reach those found with injection of 40 nmol of gluta-
mate to produce memory inhibition (Gibbs and Ng, 1979b).
Whatever the mechanism, it might seem detrimental to
prevent memory consolidation in highly stressful situations,
but Arnsten (Birnbaum et al., 1999) has suggested that in
the prefrontal cortex, where high levels of noradrenaline are
released during stress, ␣1 -AR mechanisms predominate and
switch off higher cognitive processing allowing basic sur-
vival mechanisms to control behavior. It has been suggested
that these high levels of noradrenaline may enhance cog-
nitive functioning when they occur in the posterior cortical
and subcortical areas (Ferry et al., 1999b).
6. ␣2 -Adrenoceptors
The action of noradrenaline (<1 nmol per hem) in the
hyperstriatum is prevented by blocking ␤2 - or ␤3 -ARs
(Fig. 12A–C) but not by the selective ␣2 -AR antagonist
yohimbine (Fig. 12E). However, when injected into the
LPO, the effect of noradrenaline was blocked by yohimbine
in a dose-dependent manner (Fig. 12F). When administered
s.c. yohimbine would be expected to distribute more exten-
sively than when injected intracerebrally and target more
regions of the forebrain. The antagonism of the effect of
noradrenaline injected into the LPO by yohimbine suggests
that the ␣2 -ARs responsible for the effect on memory are
located in this region.
 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391 369

Fig. 20. Enhancement of weakly reinforced learning by the ␣1 -AR antagonist prazosin injected into IMHV. Injected immediately after training, the duration
of STM is increased, the dip is shifted from the normal time of 15–25 min, a shift of 10 min. There is no effect on the duration of ITM (A) with the
second dip being at 65 min, 10 min later than the normal time of 55 min. This second 10 min difference is accounted for by the extension of STM. Time
of injection relative to training (at 0 min) shows no enhancement by prazosin given before, 10 or 30 min after training (B) (unpublished observations).

6.1. α 2 -Adrenoceptor agonists Clonidine injected into IMHV enhanced consolidation

Pilot experiments showed that the ␣2 -AR agonist cloni-
dine injected into the IMHV promoted memory consolida-
tion, but only when given 10–15 min after weakly reinforced
training. The lack of effect of yohimbine on the enhancement
of consolidation by noradrenaline injected into the IMHV
(Fig. 12E) also raised the possibility that clonidine was not
acting in this region, but being lipophilic, could be acting
at a site distal to the site of injection. The dose–response
data for clonidine injected into IMHV compared to that in
the LPO supports this interpretation. Clonidine was effec-
tive in enhancing consolidation at a lower dose in the LPO
than in the IMHV (Fig. 21A). The action of a hydrophilic
␣2 -AR agonist oxymetazoline, which would not diffuse far
from the site of injection, also supports this interpretation.
Oxymetazoline did not promote memory consolidation in-
jected into the IMHV, but was slightly more effective than
clonidine when injected into the LPO (Fig. 21).
when injected 10 and 15 min after weakly reinforced train-
ing (Fig. 22A). However, when injected into LPO, both
oxymetazoline and clonidine were effective in promoting
consolidation from 2.5 to 30 min after training (Fig. 22B and
C). When ␣2 -ARs in the LPO are stimulated by oxymetazo-
line immediately after training, the processing of memory
followed the timing of stages seen with strongly reinforced
training (Fig. 22D) with ‘dips’ in retention at 15 and 55 min
after training.
The inability of oxymetazoline to enhance memory when
injected 15 min after training is quite striking and resembles
the action of many other agonists in this review.
6.2. Specificity of action of α 2 -adrenoceptor agonists
To show that the action of clonidine was selective for
␣2 -ARs, its action was challenged by prior administration
of yohimbine at a dose that did not inhibit memory forma-

Fig. 21. Differences in the effect of ␣2 -AR agonists injected into LPO or IMHV 10 min after weakly reinforced training measured at 120 min. Clonidine
is effective at much lower doses injected into LPO than when injected into IMHV (A); whereas oxymetazoline has the same potency as clonidine in
LPO but does not enhance consolidation given at doses up to 1 pmol per hem into IMHV (B) (Gibbs and Summers, 2002).
370 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391

Fig. 22. Action of clonidine and oxymetazoline injected into LPO and IMHV. Clonidine is much more limited in the times it will promote consolidation
of weakly reinforced training when injected into IMHV (A) than when injected into LPO (C). Whereas, with IMHV injection memory consolidation
occurs only with injection 10 and 15 min after training, oxymetazoline injected into LPO (B) enhances as long as it is injected during labile memory
up to 30 min after training. The lack of effect at 15 min with oxymetazoline is more pronounced than with clonidine. Enhancement of memory when
oxymetazoline is injected into LPO at 2.5 min after weakly reinforced training (D) and test from 10 to 120 min reveals consolidation of memory with
no changes in duration of stages (Gibbs and Summers, 2002).

tion (Fig. 24A). The dose–response curves for clonidine or 6.3. α 2 -Adrenoceptor antagonists
oxymetazoline injected into the LPO 25 min after weakly
reinforced training was shifted to the right by yohimbine Yohimbine given by peripheral injection inhibits memory
(3 pmol per chick s.c.) given 15 min earlier (Fig. 23A and B). formation in a dose dependent manner (Fig. 24A). Although

Fig. 23. Challenge to enhancement of memory consolidation by the selective ␣2 -AR agonists clonidine and oxymetazoline by prior administration of
the selective ␣2 -AR antagonist yohimbine. The dose–response curve at 120 min for clonidine (A) and oxymetazoline (B) injected into LPO 25 min after
weakly reinforced training is shifted to the right of the saline curve by subcutaneous injection of a non-amnestic dose of yohimbine 10 min after training
(Gibbs and Summers, 2002).
 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
Fig. 24. Inhibition of memory of strongly reinforced training (100% anthranilate) by the ␣2 -AR antagonist yohimbine injected 10 min after learning.
Subcutaneous (A) and intracerebral injection (B). Yohimbine had greater potency injected into LPO than when injected into the IMHV (Gibbs and
Summers, 2002).
injection into the IMHV did produce a loss in memory con-
solidation at a higher dose, it was more effective at produc-
ing memory loss when injected into the LPO (Fig. 24B).
Interestingly, yohimbine given either s.c. or into the LPO
produced its inhibitory effect on memory storage when given
10 or 15 min after strongly reinforced training (Fig. 25A
and B). Memory loss, with subcutaneous injection 10 min
after training, occurred 30 min post-training (Fig. 25C). As
with the ␣1 -AR agonist, memory loss at this time implies
that the labile memory consisting of STM and ITM.A were
unaffected by the loss of the AR, but the consolidation into
long-term storage was prevented.
6.4. Conclusion
Activation of ␣2 -ARs in the basal ganglia is necessary for
the consolidation of labile memory 10–15 min after training,
at the time of formation of ITM. Differences in terms of time
of action of clonidine, the effective dose, and the inability
of yohimbine to prevent consolidation by noradrenaline in-
jected into IMHV (in contrast yohimbine blocks the effect of
noradrenaline injected into LPO), led us to conclude that the
action is on ␣2 -ARs located in the LPO. Clonidine, injected
into IMHV, probably diffuses to the site of action in the
LPO. Noradrenaline release in the LPO at 10–15 min after
training acts via ␣2 -ARs to promote memory consolidation.
Although ␣2 -ARs are present both pre- and post-
synaptically in the brain (Jarrott et al., 1980), most are
post-synaptic (U’Prichard, 1980). It has been argued that
stimulation of pre-synaptic ␣2 -ARs leads to inhibition of
noradrenaline release, and inhibition of ␣2 -ARs will lead
to an increase in extrasynaptic noradrenaline. Therefore,
yohimbine, because it leads to an increase in extrasynap-
tic noradrenaline, should enhance memory consolidation.
Indeed, there is evidence that inhibition of ␣2 -ARs by
systemic injection of the antagonist idazoxan enhances
memory (e.g. Sara and Devauges, 1989; Sara, 1991). In
contrast, peripheral and prefrontal administration of the
371
␣2 -AR agonist guanfacine improves memory in monkeys
(Arnsten et al., 1988; Avery et al., 2000). In the chick,
the ␣2 -AR antagonist rauwolscine injected into the IMHV
did decrease avoidance and presumably inhibit memory for
passive avoidance training (Stamatakis et al., 1998). In this
study, there was a suggestion that clonidine may enhance
memory formation when a relatively high dose (25 pmol per
hem) was injected into IMHV immediately after training.
As in our study, the high doses of clonidine most probably
act on ␣2 ARs in the LPO.
Conflicting reports on the inhibition of ␣2 -ARs either en-
hancing or inhibiting memory may be explained by pre- or
post-synaptic location of ␣2 -ARs, or by differences in the
dose of the antagonist. In the LoC, which would be affected
by systemic administration of antagonists, ␣2 ARs tend to be
pre-synaptic and inhibition would lead to an increase in nora-
drenaline levels. Direct injection into other regions may well
act on post-synaptic ␣2 -ARs and the action of noradrenaline
in the LPO may well be responsible for the reinforcement
of the memory stored in the hyperstriatum ventrale. The ac-
tion on ␣2 -ARs does not occur until 10 min after training, at
the end of STM in IMHV when the stages in memory pro-
cessing possibly relate to what is happening in IMHV, not
necessarily what is happening in LPO. The involvement of
LPO may be to provide the trigger to consolidate the mem-
ory in IMHV. Providing the ␣2 -ARs in the LPO are stimu-
lated by noradrenaline at 10–15 min after training, memory
consolidation is triggered in the IMHV.
As mentioned previously, the LPO is part of the basal
ganglia and is the avian homologue of the caudate putamen.
Information relating to the bitter taste, or to whether or not
a bird pecks at the bead may come from this brain region.
Csillag (1999) suggests that learned visual association with
the bead is relayed from the IMHV to the basal ganglia via
the limbic archistriatum (amygdala), the latter introducing a
motivational element. In a recent set of studies (Izawa et al.,
2001; Yanagihara et al., 2001) it has been suggested that
LPO neurones may code certain features, such as ‘quality,
372 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
Fig. 25. Effect of the ␣2 -AR antagonist yohimbine on strongly reinforced
memory. Subcutaneous injection (A) and injection into the LPO (B) only
prevented consolidation injected 10 and 15 min after training, test at
120 min (C). Subcutaneous injection at 10 min after training resulted in
memory loss 30 min after training (Gibbs and Summers, 2002).
evaluation and anticipation’ of the reward. These functions
accord with the functional roles of the mammalian striatum,
such as control of arousal, motor control and control of
goal-oriented behaviors (Schultz, 1999; Yanagihara et al.,
2001).
7. ␤1 -Adrenoceptors
The selective ␤1 -AR agonist, RO 363 (1.0–300 pmol per
hem) (McPherson et al., 1984), given into the IMHV 20 min
after training did not promote memory consolidation with
weakly reinforced training. The ␤1 -/␤2 -AR antagonist pro-
pranolol (250 nmol/kg s.c.) 15 min before RO 363 did not
affect the levels of memory retention either (Fig. 26A). RO
363 (100 pmol) per hem given to separate groups of chicks
at times between 5 min before and 30 min after training on
20% anthranilate failed to promote memory consolidation at
any of these times (Fig. 26B). In IMHV, RO 363 therefore
has no memory enhancing effect and also has no inhibitory
effect on chicks trained with 100% anthranilate.
Subcutaneous injection of the selective ␤1 -AR antagonist
CGP 20712A (100 pmol per chick) did not inhibit memory
at any time of injection between 5 min before and 30 min
after strongly reinforced training (Fig. 27) nor did it have
any effect on chicks trained on 20% anthranilate. On the
basis of these results, it is concluded that the action of the
␤1+2 -AR antagonist propranolol given 20 min after training
on memory consolidation is purely on ␤2 -ARs. However, a
preliminary study has suggested that there may be a role for
␤1 -ARs in memory formation. A discrepancy between the
effects of central (IMHV) and peripheral injection of propra-
nolol 5 min before training suggested that the peripheral in-
jection might be influencing ␤1 - or ␤2 -ARs in another brain
region at a different time. Propranolol given s.c. 5 min be-
fore training did inhibit memory formation, whereas it had
no effect when given by injection into the IMHV at this time
(see Section 8.3). The same result was seen with injection
into the LPO. When the ␤1 -AR antagonist CGP 20712A
was injected into the IMHV there was no effect (disc. ra-
tio 0.889 ± 0.039), but when it was injected into the LPO
memory formation was inhibited (disc. ratio 0.556 ± 0.049).
These preliminary results suggest a role for ␤1 -ARs in
the early stages of memory processing (STM) in the LPO.
8. ␤2 -Adrenoceptors
Moderate doses of noradrenaline or isoprenaline (1 nmol
per hem) injected into the IMHV 20 min after training en-
hance the consolidation of labile memory (Sections 4.2 and
4.4). Since the action of this dose of noradrenaline or iso-
prenaline was prevented by prior treatment with propranolol
but not CGP 20712A this action is likely to be mediated by
␤2 -ARs.
8.1. Consolidation of labile, weakly reinforced memory
by the β 2 -adrenoceptor agonist zinterol
The injection of noradrenaline (1 nmol per hem) immedi-
ately after training consolidated labile memory (Fig. 9) so
that it was still present 120 min after training. The same re-
sult was obtained with the selective ␤2 -AR agonist, zinterol
(Fig. 28A). In both cases, STM was extended by 10 min,
and the change from STM to ITM occurred at 25 instead
of 15 min. In addition, the duration of ITM was increased,
and the second dip occurred at 85–90 min. The AR agonist
 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
Fig. 26. Lack of memory facilitation by the selective ␤1 -AR agonist RO363. Response to different doses of RO363 injected 20 min after training into the
IMHV did not significantly enhance memory consolidation (A). Varying the time of injection into the IMHV (B) did not reveal any time during labile
memory when RO363 could enhance memory consolidation (Gibbs and Summers, in preparation).
Fig. 27. Lack of effect at 120 min of the selective ␤1 -AR antagonist
CGP 20,712A injected s.c. at times between 5 min before and 30 min
after 100% anthranilate training. Subsequent experiments have revealed an
effect when injection is made 10 min before training (Gibbs and Summers,
in preparation).
BRL 37344 has actions on both ␤2 - and ␤3 -ARs (Gibbs and
Summers, 2001a), and at higher doses (1 nmol per hem) acts
at ␤2 -ARs, whereas a lower dose (10 pmol per hem) acts at
␤3 -ARs (see Section 9.1). The higher dose of BRL 37344
produced the same pattern of memory retention as zinterol
and noradrenaline (1 nmol per hem) (Fig. 28C) with the du-
ration of both STM and ITM being extended. All three drugs
promoted consolidation of labile memory when injected up
to 25 or 30 min post-training, i.e. while labile memory is still
present (Figs. 9A and 28B,D). Once labile memory weak-
ened, the drugs were no longer able to promote consolida-
tion. The weaker effect of noradrenaline and zinterol when
injected at 15 min (Figs. 9A and 28B) is a consistent, but
as yet unexplained phenomenon. It may indicate that these
drugs have exactly the same effect throughout the duration
of labile memory, but that another event occurs at 15 min to
decrease the enhancement of memory.
373
8.2. Specificity of the action of zinterol on β 2 -adrenoceptors
The specificity of the action of zinterol for ␤2 -ARs is
easily shown. The dose–response curve to zinterol, injected
at 20 min after weakly reinforced training, was shifted to
the right by prior administration of propranolol (Fig. 29).
The dose of propranolol was selected (Fig. 30) as one that
did not inhibit strongly reinforced training. On the other
hand, the dose–response curve to zinterol was not shifted
by prior administration of the selective ␤3 -AR antagonist
SR 59230A (Fig. 29).
8.3. Inhibition of strongly reinforced memory by the
β 1+2 -adrenoceptor agonist propranolol
Propranolol inhibits memory consolidation when injected
both centrally and peripherally. Propranolol is lipophilic
and crosses the blood–brain barrier in mammals. A lower
dose is more effective in producing memory inhibition when
given into the brain than when given s.c. (Fig. 30). 10 nmol
per hem inhibits memory, whereas 30 nmol per chick s.c.
results in the same level of memory inhibition. The times of
injection for inhibition of memory by propranolol are dif-
ferent when given intracranially (i.c.) than when given s.c.
8.3.1. Subcutaneous administration of propranolol
Propranolol is effective in inhibiting memory when
injected between 5 min before and 25 min after strongly re-
inforced training (Fig. 31A), whereas injection 30 min after
training has no effect on memory. When memory retention is
tested following injection at 5 min (Fig. 31C) after training,
memory loss occurs after 30 min post-training, and memory
does not consolidate. These results are identical with those
reported by Stephenson and Andrew (1981), where the ␤-AR
antagonist sotalol was amnestic when injected 10–25 min
after training, but not 30–60 min after training. Memory loss
occurred over ITM.B. Note that propranolol given imme-
374 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391

Fig. 28. Memory enhancement seen at different times of test following activation of ␤2 -ARs by zinterol or BRL 37344 (100 pmol per hem) injected
immediately after training into the IMHV. Both drugs extended the duration of STM and ITM (A and C). Saline injected chicks (C) showed no evidence
of memory enhancement 100 or 120 min after training. Both agonists were ineffective in enhancing weakly reinforced learning when injected 30 or
more min after training, when labile memory in saline treated chicks had decayed (B and D) (adapted from Gibbs and Summers, 2000, 2001a).

diately after or 20 min after training, produces less memory

loss than at the other times. These two time points have
been repeated with identical results. The explanation for this
finding may lie in an increase in endogenous levels of nora-
drenaline at the time of learning such that a higher dose of
propranolol is required at these times to effectively inhibit

Fig. 29. Specificity of action of ␤2 -AR agonist zinterol in enhancing

weakly reinforced learning. Zinterol was injected 20 min after training
after pre-administration of subcutaneous propranolol 5 min after training
(Fig. 10). Propranolol shifted the dose–response curve for zinterol to the
right. The selective ␤3 -AR antagonist SR 59230A did not shift the curve
(adapted from Gibbs and Summers, 2000).
Fig. 30. Prevention of memory by different doses of propranolol injected
into the IMHV or s.c. 10 min after training on 100% anthranilate (Gibbs
and Summers, in preparation).
 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391 375

memory. Increasing the dose of propranolol to 300 nmol
per chick with injections at 0 and 25 min after training pro-
duces the level of memory loss seen at the other times of
injection.
The amnestic potency of a drug can be influenced by the
timing of the injection, if the injection itself is ‘arousing’
or aversive, increasing endogenous noradrenaline release
(Benloucif et al., 1990). Thus, the stress associated with
the use of a ‘head holder’ to make injections immediately
post-training may produce amnesia by an excessive release
of noradrenaline (Sandi and Rose, 1994). These results could
be interpreted in terms of central noradrenaline release with
arousal or stress interfering with the action of the drug in
producing memory inhibition.
In the present study, injection of propranolol 5 min be-
fore training resulted in memory loss as early as 10 min
after training (Fig. 31D). A similar result was reported by
Stephenson and Andrew (1981) where the injection of the
␤2 -AR antagonist sotalol 5 min before training caused mem-
ory loss by 10 min after training. This result suggests that
propranolol and sotalol may have more than one action on
memory depending on when the injection is made (i.e. the
stage the memory processing is at). Whether the effect is due
to ␤1 -activation alone or on both ␤1 - and ␤2 -AR activation
is not yet clear.
8.3.2. Intracranial administration of propranolol
In contrast to the results seen with peripheral admin-
istration of propranolol, intracerebral injection into the
hyperstriatum ventrale results in memory loss following
injection from 5 to 25 min after training (Fig. 31B). Pro-
pranolol did not inhibit memory consolidation at the earlier
times seen with subcutaneous administration, i.e. between
5 min before and 2.5 min after training. This suggested that
there was another site of action of propranolol distinct from
the IMHV that is targeted by subcutaneous injection. With
injection of propranolol at 5 min after training, memory
loss occurs after 30 min as with subcutaneous injection
and memory consolidation is prevented. The results of a
preliminary study showed that injection of propranolol into
the LPO was effective in inhibiting memory in a similar
manner to a subcutaneous injection. Injection into the LPO
5 min after training was ineffective. When propranolol is
injected into the LPO, or given s.c. 5 min prior to training,

Fig. 31. Inhibition of strongly reinforced memory by propranolol depending on the time and location of the injection. Subcutaneous propranolol prevented
memory consolidation when injected from 5 min before to 25 min after training with the exception of injection immediately after and 20 min after (A).
When injected into the IMHV, propranolol was less effective and prevented memory only from 5 to 25 min after training, not when injected before training
(B), When tested at different times up to 120 min, both subcutaneous and IMHV injection 5 min after training resulted in memory loss after 30 min (C).
Injection into s.c. 5 min before training resulted in memory loss by 5 min after training (D). Injection at other times into LPO did not prevent memory (not
shown) (Gibbs and Summers, in preparation). These results suggest that propranolol acts on ␤1 - and ␤2 -ARs at different times in memory processing.
376 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
memory is impaired when the chicks are tested from 10 min
post-training (Fig. 31D).
As discussed in the previous Section, it is quite likely that
this effect involves an action on ␤1 -ARs, although an effect
on ␤2 -ARs cannot be ruled out because the ␤2 -AR agonist
zinterol increased the duration of STM.
8.4. Conclusion
Activation of ␤2 -ARs is important for the consolidation of
memory. The ␤2 -AR agonist zinterol will promote consoli-
dation of a labile, weakly reinforced memory. The ␤1+2 -AR
antagonist propranolol injected into the IMHV after strongly
reinforced training will prevent memory consolidation, prob-
ably by blocking ␤2 -ARs at the time of ITM. There appears
to be no involvement of ␤1 -ARs in memory formation over
this time period and in this brain region. On the other hand,
␤1 -ARs may be involved in the LPO at the time of learn-
ing, and propranolol administered in this location and at this
time will prevent or inhibit STM formation. ␤1 -ARs could
also be involved in attention or arousal phenomena at the
time of learning. An action on STM is supported by the abil-
ity of zinterol and noradrenaline (1 nmol per hem) to extend
the duration of STM; an action on ITM is supported by the
extension of ITM.
There are several potential candidate mechanisms for
␤2 -AR involvement in memory formation. Noradrenaline
has actions that influence astrocytic metabolism and neu-
ronal activity, which are possibly directed through ␤2 -ARs.
Noradrenaline promotes the breakdown of glycogen thus
providing additional energy at a time of peak demand, at
the point of consolidation of memory (Hertz et al., 1996).
In the CNS, glycogen is stored mainly in astrocytes and is
available for rapid release. The metabolic inhibitor iodoac-
etate injected into IMHV 25 min after training prevents
memory consolidation (O’Dowd et al., 1994a; Hertz et al.,
1996). There is a significant breakdown in glycogen levels
55 min after training (O’Dowd et al., 1994b). Two drugs
which interfere with glycolysis and glycogenolysis, iodoac-
etate (O’Dowd et al., 1994a) and 2-deoxyglucose (Gibbs
and Summers, in press) also prevent the consolidation of
memory past 30 min when injected into the IMHV 25 min
after training. Iodoacetate or 2-deoxyglucose injected into
the LPO has no effect on memory consolidation; in the
LPO the noradrenaline effect on ␤-ARs is on ␤1 -AR.
Noradrenaline, applied to primary astrocyte cultures
prepared from neonatal mouse brain, promotes a rapid
and concentration-dependent glycogen breakdown with the
maximal effect reached within 5 min (Sorg and Magistretti,
1991). Noradrenaline exerts a second, temporally delayed
increase in glycogen in astrocytes apparent 1–2 h later (Sorg
and Magistretti, 1992). This effect occurs with a 1 min pulse
of 100 ␮M noradrenaline or isoprenaline, and is dependent
on protein synthesis and PKA (Sorg and Magistretti, 1992).
Noradrenaline upregulated the expression of glycogen syn-
thase mRNA in astrocytes but not in neurones (Pellegri
et al., 1996) and stimulated protein targeting to glycogen
mRNA expression in mouse cortical astrocytes.
The localization of ␤-ARs in the rat visual cortex is pri-
marily on astrocytes (Aoki, 1992). Although there has been
some disagreement as to the subtypes of ␤-ARs located on
astrocytes in culture, it is clear that in vivo, astrocytes express
␤2 -ARs in a wide variety of brain areas (Mantyh et al., 1995).
Physiologically, ␤-ARs have been implicated in the
signal-to-noise ratio in the cerebral cortex (Waterhouse et al.,
1982). The predominantly inhibitory effect of noradrenaline
on spontaneous discharge of cortical neurones would lead
to an increase in the signal-to-noise ratio and enhancement
of incoming signals (Aston-Jones, 1985). Noradrenaline
will increase Na+ /K+ ATPase activity, and in chick brain
total homogenate the effect of noradrenaline on Na+ /K+
ATPase activity is via ␤-ARs (Jeffrey and Gibbs, 1976).
Noradrenaline and isoprenaline produced a dose-dependent
increase and propranolol a decrease in Na+ /K+ ATPase ac-
tivity in total homogenate. The ␣-AR agonist methoxamine
and the antagonist piperoxane had no effect on Na+ /K+
ATPase activity. There was only a slight stimulation of
Na+ /K+ ATPase by noradrenaline in the synaptosomal
fraction. These experiments do not reveal what function
the ␤-AR stimulation of Na+ /K+ ATPase activity has in
vivo but does perhaps discriminate between ␤2 - and ␤3 -AR
effects since isoprenaline will stimulate all ␤-ARs includ-
ing ␤3 -ARs, but propranolol will inhibit only ␤1 - and
␤2 -AR.
The model proposed by Pellerin and Magistretti (Pellerin
and Magistretti, 1994; Magistretti and Pellerin, 1999a,b)
is of interest in the context of the function of astrocytic
Na+ /K+ ATPase in removing sodium ions taken up with
excess glutamate associated with neural activity. If nora-
drenaline stimulates Na+ /K+ ATPase activity, it may be
responsible for limiting the excitatory action of glutamate
at the synapse by enhancing the increased signal-to-noise
ratio. Another function of increased Na+ /K+ ATPase ac-
tivity in astrocytes is its stimulation of glucose uptake and
the breakdown of glycogen, the latter being a phenomenon
of noradrenergic stimulation of astrocytes. The increased
supply of energy as a consequence of glycogen breakdown
or by glycolysis is fed back to the neurones in the form
of lactate. The increased uptake of glucose, is not a re-
sult of ␤2 -AR activation, but is the consequence of ␤3 -AR
activation as will be described in the Section 9.
9. ␤3 -Adrenoceptors
9.1. Consolidation of labile, weakly reinforced,
memory by β 3 -adrenoceptor agonists
The action of low doses of noradrenaline (0.1 nmol per
hem) in promoting memory consolidation was prevented by
prior administration of the selective ␤3 -AR antagonist SR
59230A (Gibbs and Summers, 2000). However, the enhanc-
 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391 377

Fig. 32. Memory enhancement following activation of ␤3 -ARs. The selective ␤3 -AR agonist CL 316243 injected into the IMHV 20 min after weakly
reinforced training promotes the consolidation of memory and appears to reinstate the memory (A) in that the duration of STM and ITM are the same
as with strongly reinforced training. When the time of injection of CL 316243 is between −5 and 25 min after training it enhanced consolidation up to
25 min after training (B) (adapted from Gibbs and Summers, 2000).

ing effect of higher doses of noradrenaline was not altered

by SR 59230A indicating activation of ␤2 -ARs.
The selective ␤3 -AR agonist CL 316243 promoted mem-
ory consolidation when injected at times ranging from 5 min
before to 25 min after weakly reinforced training (tested at
120 min). As with noradrenaline (Fig. 9), CL 316243 had
to be injected whilst labile memory was present. When
injected 30 min post-training or later CL 316243 had no
effect on memory consolidation (Fig. 32B). When injected
immediately after training, memory consolidation was re-
instated and memory at the different times after training
was the same as when chicks were subjected to strongly
reinforced training (Figs. 2B and 32A). In contrast, 1 nmol
per hem of noradrenaline increased the duration of the dif-
Fig. 33. Dose–response curves to different drugs with potential ␤3 -AR
ferent stages, whereas the ␤3 -AR agonist did not alter the
activity. Dose–response relationships for three different ␤3 -AR ago-
duration of the memory stages. The timing of the stages nist—CGP 12177A, BRL 37344, SR 56,811 are compared to that of CL
with the ␤3 -AR agonist was the same as that with training 316243. The agonists were injected 20 min after weakly reinforced train-
on 100% anthranilate. ing and memory tested 120 min after training. SR 56811 did not enhance
To determine whether CL 316243 was prototypical of all memory (see text) (adapted from Gibbs and Summers, 2001a).
␤3 -AR agonists, others were tested (Gibbs and Summers,
2001a,b). Dose–response relationships of BRL 37344, CGP has a different profile acting as a ␤3 -AR partial agonist, and
12177A, and SR 58611 were compared with that of CL a potent antagonist at ␤1 - and ␤2 -ARs. The action of low
316243 (Fig. 33) and those for BRL 37344 and CGP 12177A doses of CGP 12177A (1.0 and 3.0 pmol per hem) were
were similar to that of CL 316243. SR 58611 originally reduced by SR 59230A (Fig. 34D) whereas propranolol had
developed as a gut specific ␤3 -AR agonist (Bianchetti and no effect (Fig. 34C).
Manara, 1990) and was only effective at a high dose. This When a low dose of BRL 37344 is injected immedi-
compound is believed to act via an active metabolite formed ately after weakly reinforced training (Fig. 35B), memory
by de-esterification in the wall of the colon, and the esterases is reinstated without any alteration in the duration of the
may not be present in chick brain. memory stages. A low dose of noradrenaline (0.1 nmol per
BRL 37344 has a biphasic action—at low doses it acts hem, Fig. 35A) also reinstates memory, and shows the same
on ␤3 -ARs, but at higher doses it also acts on ␤2 -ARs timing with dips in retention at 15 and 55 min.
(Fraeyman et al., 1992; Lui et al., 1996). The actions of a
low dose of BRL 37344 (10 pmol per hem) injected into 9.2. Specificity of action of β 3 -adrenoceptor agonists
IMHV 20 min after weakly reinforced training were reduced
by the ␤3 -AR specific antagonist SR 59230A (Fig. 34B) In order to determine whether CL 316243 was acting
whereas the effect of higher doses (0.3 and 1.0 nmol per specifically at ␤3 -ARs, a dose–response relationship was
hem was reduced by propranolol (Fig. 34A). CGP 12177A established for CL 316243, which was challenged by
378 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391

Fig. 34. Dose–response curves to ␤3 -AR agonists challenged by selective ␤2 - and ␤3 -AR antagonists propranolol and SR 59230A. BRL 37344 (A and
B) and CGP 12177 (C and D) injected 20 min after weakly reinforced training were challenged by subcutaneous administration of non-amnestic doses
of propranolol; SR 59230A 5 min post-training (Fig. 10) (Gibbs and Summers, 2001a). Low doses of BRL 37344 were successfully challenged by
the ␤3 -AR antagonist and higher doses by the ␤1 -/␤2 -AR antagonist propranolol. Memory enhancement by CGP 12177A on the other hand, was only
challenged by SR 59,230 and not by propranolol.

prior administration of the selective ␤3 -AR antagonist SR
59230A or propranolol. As the antagonist inhibits memory
at higher doses, the dose chosen was one that had minimal
inhibitory effects on memory. Chicks were given graded
doses of the agonist by bilateral intracranial injection 20 min
after training, and the dose–response curve compared to the
dose–response curve obtained in the presence of each of the
antagonists given s.c. 5 min after training. The peripheral
route of administration of the antagonists was chosen to
reduce any possible damage to the region of the brain used

Fig. 35. Reinstatement of memory retention following weakly reinforced training following injection of a low dose of noradrenaline (A) or a low dose
of BRL 37344 (B). This pattern is typical of ␤3 -AR agonists with the dips occurring at 15 and 55 min as seen with CL 316243, supporting the results
suggesting that 100 pmol per hem of noradrenaline is acting via ␤3 -ARs (Gibbs and Summers, 2001a).
 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
Fig. 36. Specificity of action of CL 316243 on ␤3 -ARs. The ␤3 -AR
agonist was injected into IMHV 20 min after weakly reinforced training
using the protocol shown in Fig. 10. The dose–response curve to CL
316,243 was challenged by subcutaneous pre-administration of the selec-
tive ␤3 -AR antagonist SR 59230A 5 min after training (20% anthranilate).
The dose–response curves were shifted to the right in a dose dependent
manner. The curve was not shifted by prior administration of propranolol
(adapted from Gibbs and Summers, 2000).
for injection of the agonist. Access of the antagonists to the
brain is unlikely to be impaired by peripheral administration
since the blood–brain barrier of the 1-day-old chick is not
fully developed (Liebner et al., 1997).
The dose–response curve for the facilitation of memory
formation by CL 316243 tested at 120 min was shifted to
the right in a parallel fashion by prior administration of SR
59230A (∼75 or 250 pmol/kg) in a dose-dependent manner,
but was not altered by propranolol (250 nmol/kg; Fig. 36).
9.3. Inhibition of memory formation by β 3 -adrenoceptor
antagonists
The ␤3 -AR antagonist SR 59230A inhibited memory
formation in a dose-dependent manner (Fig. 37). When
administered 5 min after strongly reinforced training, sub-
cutaneous SR 59230A inhibited memory formation (tested
at 120 min). The dose of 30 pmol per chick (∼750 pmol/kg)
was used in subsequent experiments to determine the point
in the memory processing sequence where the inhibition
occurred.
SR 59230A was only effective in inhibiting memory for-
mation when injected s.c. 5 min after strongly reinforced
training (Fig. 38A). At all other times after training, it failed
to inhibit memory formation. Intracerebral injections into
the IMHV produced similar results, with maximum memory
loss following injection 5 min post-training; the only differ-
ence being a slight inhibition with injections immediately
and 10 min after training (data not shown). Memory loss
with SR 59230A injected 5 min post-training (Fig. 38B)
379
Fig. 37. Subcutaneous dose–response relationship to the ␤3 -AR antagonist
SR 59230A injected 5 min after strongly reinforced training (Gibbs and
Summers, in preparation). Memory tested 120 min after training.
occurred by 20 min after training. STM was intact, but there
was no phase A of ITM.
The very limited susceptibility to interference by the
␤3 -AR antagonist is puzzling, since no other agent has
such a short time in which it can act. Because these chicks
were trained with 100% anthranilate on the bead, there
would be release of endogenous noradrenaline, which pre-
sumably acts on ␤2 - as well as ␤3 -ARs, to produce LTM
retention. Therefore, it is possible that higher levels of
noradrenaline acting via ␤2 -ARs are the dominating in-
fluence on memory formation in this situation. One might
expect that the endogenous levels of noradrenaline fol-
lowing weakly reinforced training would be lower than
with strongly reinforced training, and hence the effect of
the ␤3 -AR antagonist would be more pronounced. Chicks
given weakly reinforced training, then injected s.c. with SR
59230A 5–25 min post-training and tested at 30 min after
training showed that SR 59230A effectively inhibited labile
memory at all times of injection (Fig. 38C). Injected at 5 or
10 min after weakly reinforced training, SR 59230A caused
memory loss as early as 20 min after training (Fig. 38D).
Inhibition of memory by the selective ␤3 -AR agonist—SR
59230A resulted in loss of memory as early as 20 min after
training with both weakly or strongly reinforced training.
With strongly reinforced training, it is possible that the effect
of this AR-antagonist was masked by endogenous release of
noradrenaline at times other than 5 min post-training, acting
on ␤2 -ARs.
9.4. Conclusion
The mechanism of ␤3 -AR activation on memory for-
mation appears to be related to the uptake of glucose into
cells, probably astrocytes. The ␤3 -AR agonist CL 316243
enhances the facilitatory effect of glucose on memory con-
solidation (Gibbs and Summers, in press), in contrast to the
␤2 -AR agonist zinterol and the ␣1 -AR antagonist. In addi-
tion, CL 316243 produces memory loss with a non-amnestic
dose of 2-deoxyglucose. This only occurs when the agonist
380 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391

Fig. 38. Inhibition of memory by the ␤3 -AR antagonist SR 59,230. The time of injection that inhibits memory with 100% anthranilate training is limited
to 5 min after training (A); and memory is lost after 10 min and ITM is prevented (B). When chicks are trained on 20% anthranilate, memory is susceptible
to inhibition at more injection times (C). Memory loss is again after 10 min with weakly reinforced training (D). It is suggested that endogenous release
of noradrenaline with 100% anthranilate training recruits ␤2 -ARs which are not inhibited by the ␤3 -AR antagonist (Gibbs and Summers, in preparation).

and 2-deoxyglucose are injected at the time of consolida-
tion, not earlier during STM or at the time of acquisition.
These results suggest that noradrenaline, acting via ␤3 -
ARs, causes increased uptake of glucose into astrocytes dur-
ing the first part of ITM, just prior to memory consolidation.
10. Peripheral administration of noradrenaline
The effects of noradrenaline and adrenergic agonists
in this review have been produced, for the most part, by
injection directly into the brain. This was intended to mimic
the intracerebral release of noradrenaline from nerve termi-
nals in the cortex and other brain regions, upon stimulation
of adrenergic cell bodies in the LoC and other brain stem
adrenergic brain centers.
Foot shock and other noxious training stimuli increase
plasma levels of noradrenaline and adrenaline released from
the adrenal medulla. It is unlikely, at least in mammals, that
the increased peripheral levels of noradrenaline cross the
blood–brain barrier and there has been debate as to how
the effects on memory are achieved (Gold, 1995; Williams
et al., 1998). Because the blood–brain barrier is not fully
mature at hatch, it is not known whether the effects seen in
the chick with systemic administration are central or due to
a peripheral effect of noradrenaline.
In accord with this finding, subcutaneous injection of no-
radrenaline (25 and 150 ␮g/kg; 3.1 and 18.8 nmol per chick;
1 and 6 ␮g per 100 ␮l) promoted consolidation of weakly
reinforced training, but only when given 5 min before or
immediately after training (Crowe et al., 1990).
Injection of the higher dose of noradrenaline (18.8 nmol
per chick) enhanced memory consolidation and extended
the duration of ITM without effect on the duration of STM
(Fig. 40B). Subsequently, it was found that subcutaneous
injection of noradrenaline (0.1 nmol per chick) immediately
after training consolidated memory formation (Fig. 39).
Administration of noradrenaline (1.0 nmol per chick)
over different times produced a biphasic curve (Fig. 40A),
where injection from −5 to +2.5 min and from 20 to 30 min
after training enhanced consolidation, whereas injection
at 5–15 min after training had no effect. A dose–response
curve with noradrenaline injected at 5 min after training
revealed that a higher dose of noradrenaline was able
to enhance consolidation (Fig. 39). A preliminary study
showed subcutaneous zinterol to have a similar pattern in
terms of times when it enhanced weakly reinforced learn-
ing (Fig. 40A), whereas CL 316243 did not show the same
 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
Fig. 39. Dose–response to s.c. administered noradrenaline on chicks
trained with 20% anthranilate. Noradrenaline was injected immediately
or 5 min after training. Higher doses are necessary to promote consoli-
dation with administration 5 min compared to injection immediately after
training (unpublished observations).
pattern. Whether this difference is due to the route of
administration is unknown at this stage.
Which adrenoceptors is noradrenaline acting on?
The effects of noradrenaline given peripherally will
be complicated by central release of endogenous trans-
mitter. The results suggest that there is central release
of noradrenaline immediately after and at around 20 min
after training (i.e. just before consolidation). The action
of peripherally administered noradrenaline at these times
would be expected to be different from times when there is
no centrally released transmitter.
This pattern was repeated in experiments where nora-
drenaline was used to challenge the inhibitory effect of the
protein synthesis inhibitor anisomycin on memory forma-
tion. Anisomycin injected 5 min before strongly reinforced
Fig. 40. Effect of subcutaneous injection of noradrenaline, CL 316,243 and zinterol on enhancement of weakly reinforced training. The time of injection
of noradrenaline and zinterol show very similar effects (A), however CL 316,243 is not the same. This is in accord with the action of 1 nmol of
noradrenaline acting via ␤2 -ARs. Time of test following injection immediately after training revealed an extension of ITM but no effect on STM which
remains at 10 min duration (B) (unpublished observations).
381
training, causes loss of memory after 50 min but labile mem-
ory remains intact (Gibbs and Ng, 1977). Noradrenaline
is effective in challenging anisomycin when given imme-
diately after training and again at 20–40 min after training
(Fig. 41A). This pattern is similar to that seen with weakly
reinforced training and noradrenaline (Fig. 40A) injected at
different times into IMHV.
The evidence suggests that noradrenaline extends the du-
ration of the second half of ITM (ITM.B). Dinitrophenol
(2,4-DNP), an inhibitor of oxidative metabolism inhibits
ITM.A but has no effect on ITM.B (Gibbs and Ng, 1984a)
and can be used as a diagnostic tool to determine the dura-
tion of ITM.A. DNP is effective at the same times as con-
trols with no injection of noradrenaline, with both 2 and 6 ␮g
of noradrenaline (Fig. 41B), therefore the extension of ITM
seen with noradrenaline is not due to a change in duration
of ITM.A.
Anisomycin inhibits LTM formation given up to 20 min
after training (Fig. 41C). When chicks are given nora-
drenaline (s.c.) immediately after training as well as an
intracerebral injection of anisomycin at different times after
training (Fig. 41C), there is no change in the time of effec-
tiveness of anisomycin. This means that the onset of LTM
formation occurs at the interface of ITM.A and ITM.B. The
increased duration of ITM caused by noradrenaline is dose
dependent—2 ␮g/100 ␮l of noradrenaline shifts the second
dip in memory storage from 55 to 70 min, 4 ␮g/100 ␮l to
80 min and 6 ␮g/100 ␮l to 85 min (data for 6 ␮g/100 ␮l in
Fig. 40B, other data not shown).
Although there is information on the action of periph-
erally administered adrenaline, and the effects of centrally
administered AR antagonists in the rat (e.g. Gold, 1995),
at this stage it is not known what effect peripheral no-
radrenaline has on central ARs with respect to memory
formation and consolidation in the day-old chick because
noradrenaline can enter the central circulation.
382 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
Fig. 41. Characterization of effect of noradrenaline on ITM phase B.
Noradrenaline injected at different times after training with anisomycin
injected 5 min prior to training is effective in challenging the amnestic
effect of anisomycin over two time periods—immediately after and again
after 20–30 min post-training, i.e. it has no effect during ITM.A (A).
By varying the time of injection of the metabolic inhibitor 2,4-DNP, the
duration of ITM.A was not changed in the presence of noradrenaline
(B). The timing of the offset of the ability of anisomycin to prevent
consolidation is not altered in the presence of noradrenaline injected
immediately after training (C) (unpublished observations).
11. Summary of the action of different adrenoceptors
at different times and in different brain locations
Evidence has been presented for the roles of nora-
drenaline in the forebrain mediated by actions on different
AR subtypes located in two regions. Memory formation
and consolidation into long-term storage in the chick in a
one-trial discriminated avoidance task requires the action
of noradrenaline on different ARs in the IMHV (associa-
tion cortex) and the LPO (basal ganglia-caudate putamen).
There are two stages where noradrenaline has an important
influence on memory formation. There is an effect early
during STM and later on the consolidation of labile mem-
ory into a permanent store. The latter is triggered 30 min
after weakly reinforced training and in these experiments
is achieved by injection of noradrenaline 20 min after train-
ing. Obviously, noradrenaline has multiple roles in memory
formation and consolidation. Preventing the consolidation
of labile memory into long-term storage can be achieved
by a wide variety of agents from pharmacological to be-
havioral, which may disrupt the trigger leading to memory
consolidation rather than inhibiting the cellular mechanisms
responsible for the memory.
11.1. Consolidation of memory by administration
of noradrenaline
Consolidation from a labile store to long-term storage
is achieved by injection of noradrenaline at 20 min after
training. A low dose of noradrenaline (100 pmol per chick)
injected into the IMHV (association cortex) immediately
after weakly reinforced training (20% anthranilate) rein-
states memory without altering the duration of STM or ITM
(Fig. 35A). A higher dose (1.0 nmol per chick) injected
into the IMHV also enhances consolidation for weakly re-
inforced training (Fig. 9A), but the duration of STM and
ITM are both extended. However, if the dose is very high
(3 or 10 nmol per hem), there is memory loss due to failure
of consolidation. The evidence based on the responses to
selective AR agonists and antagonists, suggests that the
difference between these doses of noradrenaline is due to a
differential effect on ␤2 - and ␤3 -ARs in the IMHV.
11.2. Involvement of β 2 - and β 3 -adrenoceptors
in IMHV
As noradrenaline release in the IMHV gradually in-
creases, ␤3 - then ␤2 -ARs will be progressively activated.
The effect of the selective ␤3 -AR antagonist SR 59230A and
the ␤1+2 -AR antagonist propranolol at different doses of
noradrenaline supports this view. As ␤1 -AR agonists and an-
tagonists do not influence memory consolidation at this time,
propranolol must be acting via ␤2 -ARs. ␤3 -AR agonists in-
jected immediately after training reinstate the memory pro-
cessing, whereas the ␤2 -AR agonist produces an extension
of both STM and ITM in the same manner as intermediate
doses of noradrenaline. There is a gradual increase in nora-
drenaline levels in the forebrain of the chick between 10 and
30 min after training dependent on the level of anthranilate
used in training (Crowe et al., 1991a). Noradrenaline will
first act on ␤3 -ARs and then, as the levels increase, ␤2 -ARs
in the IMHV are recruited for the consolidation of memory.
Injection of even higher doses of noradrenaline (10 nmol
per hem) inhibits memory consolidation. This action is
mediated by ␣1 -ARs since there is no inhibitory effect of
high doses of the ␤-AR agonist isoprenaline that has no
␣1 -AR activity. In addition, the ␣1 -AR agonist methoxam-
ine mimics the effects of high dose noradrenaline that is
 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391 383

prevented by prior administration of the selective ␣1 -AR
agonist prazosin. The timing of memory loss when selec-
tive antagonists are injected relative to strongly reinforced
training (100% anthranilate) also supports the idea that ␤3 -
and ␤2 -ARs have different roles.
Inhibition of ␤3 -ARs by the selective antagonist SR
59230A causes a loss of the first part of ITM (ITM.A),
whereas inhibition by propranolol depending on the time of
injection, inhibits STM or consolidation into long term stor-
age by ␤1 - or ␤2 -ARs, respectively. The anomaly between
the level of reinforcement of training (20% versus 100%
anthranilate) and the times at which inhibition of ␤3 -ARs
produces loss of memory may be explained by differences in
release of endogenous noradrenaline with weak and strong
levels of reinforcement. Inhibition of memory formation by
SR 59230A occurs only at 5 min after strongly reinforced
training, but occurs throughout the duration of ITM.A with
weakly reinforced training. With strong training, as the
endogenous release of noradrenaline increases ␤2 -ARs are
recruited and mask the inhibitory effect of ␤3 -AR antago-
nists. Because this does not happen at 5 min post-training,
this may represent the onset of the reinforcing influence of
noradrenaline.
This is a potential problem that may occur in studies
using other drugs to inhibit memory formation. The endoge-
nous release of noradrenaline, as the consequence of LoC
stimulation by arousal, etc. may complicate interpretation
of results from administration of other noradrenergic and
non-noradrenergic inhibitors. It is also possible that other
drugs could influence memory by action on endogenously
released noradrenaline. As can be seen with propranolol,
different effects can be obtained with the same drug depen-
dent on the time and route of administration. Propranolol,
injected from 5 to 25 min after strongly reinforced training,
interferes with consolidation of labile memory, whereas in-
jected 5 min before training interferes with STM, the latter
effect by an action on ␤1 -ARs. The variation in effective-
ness with subcutaneous injections may also reflect changes
in endogenous release of noradrenaline (Fig. 42).
11.3. Involvement of α 2 - and β 1 -adrenoceptors in
the basal ganglia (LPO)
Injection of noradrenaline into the LPO also enhances
memory consolidation in a similar dose-dependent man-
ner to injection into the IMHV. However, the action of

Fig. 42. Model of interaction of ARs in two locations at different times after learning. (A) Incoming information from taste and visual systems is
responsible for ‘arousal’ induced stimulation in the LoC and noradrenaline release in the LPO where ␤1 -ARs are activated during STM. At the same
time or at least by ITM phase A, ␤3 -ARs are activated by LoC induced noradrenaline in the IMHV. (B) Whether or not these areas feed back to the
LoC directly or via another neurotransmitter system, there is further noradrenaline release in the LPO which activates ␣2 -ARs, which in turn increases
the noradrenaline release in the IMHV which activates ␤2 -ARs and leads to the consolidation of memory.
384 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
noradrenaline in the LPO is prevented by prior administra-
tion of the ␣2 -AR antagonist yohimbine, but not by either
␤2 - or ␤3 -AR antagonists. Yohimbine had no effect on the
dose–response relationship to noradrenaline injected into the
IMHV.
Although the ␣2 -AR agonist oxymetazoline will promote
consolidation of weakly reinforced memory for up to 30 min
after training, the times when the ␣2 -AR antagonist inhibits
memory consolidation are more restricted than when the
␤2 - or ␤3 -AR antagonists are injected into the IMHV, and
yohimbine only prevents consolidation when injected 10 or
15 min after training. The discrepancy between the timing
of the agonist and the antagonist is puzzling and may be the
result of yohimbine having an enhancing effect elsewhere
in the brain (e.g. LoC). The hydrophilic agonist oxymeta-
zoline would not be expected to diffuse far from the site of
injection.
The restricted time of effect of the lipophilic ␣2 -AR ag-
onist clonidine when injected into IMHV (only enhancing
at 10 and 15 min after training) suggested that this drug dif-
fused to the LPO where it had its action. This is supported
by the extended duration of action (up to 30 min) when
injected into LPO and by the shift in the dose–response
curve to the left with LPO injection, the optimum dose in
LPO being 0.03 pmol per hem compared to 1.0 pmol per
hem injected into IMHV. In addition, oxymetazoline, which
has the same affinity as clonidine in the LPO, does not
enhance memory when injected into IMHV. In conclusion,
the results suggest that noradrenaline acts on ␣2 -ARs in the
LPO in series with IMHV.
The role of ␣1 -ARs in IMHV may be tied to stress. With
high levels of (-)-noradrenaline, ␣1 -ARs are activated to
inhibit consolidation of memory. (Birnbaum et al., 1999;
Arnsten, 2000). However, the influence of stress on mem-
ory formation is clearly more complex, and as with nora-
drenaline, the stress hormone corticosterone can facilitate
or inhibit memory depending on dose (Sandi and Rose,
1997; Gibbs and Summers, unpublished observations). No-
radrenaline interacts with glucocorticoids via ␣- and ␤-ARs
(Roozendaal et al., 2002; Gibbs and Summers, unpublished
observations).
In conclusion, STM involves modulation by noradrenaline
acting on ␤1 -ARs in the LPO; and the first part of ITM
requires noradrenergic modulation via ␤3 -ARs in the region
of the IMHV. From 10 min after training, if there is sufficient
activation of ␣2 -ARs in the LPO, noradrenaline promotes
the consolidation of labile memory.
12. Hypothesis for the role of noradrenaline
in memory consolidation
Noradrenaline, whilst it may only modulate memory
consolidation, is critical for memory formation. Release
of noradrenaline at the time of learning is necessary for
␤1 -AR activation in the LPO (basal ganglia) where it is
necessary for the formation of STM and subsequently
there is an action on ␤3 -ARs in the IMHV. Further release
of noradrenaline in the LPO follows acting on ␣2 -ARs,
which influences (perhaps by feedback to the LoC) ac-
tivities occurring in the IMHV. The trigger for release of
noradrenaline that acts on the ␤2 -ARs must come from
LoC or some related noradrenergic neurones in the brain
stem.
12.1. Consequences of activation of adrenoceptors
to memory formation
There are a number of different aspects of the activation
of receptors by noradrenaline in the brain. As well as the
pharmacological actions of the selective drugs, the con-
sequences of activation can be viewed in terms of either
metabolic effects or physiological effects.
12.1.1. Metabolic consequences
The metabolic consequences of activation of ␤3 -ARs
includes an increase in uptake of glucose. ␤2 -ARs also
increase energy supply within the brain by stimulating the
breakdown of glycogen in astrocytes. There are a number
of activities for which this increased energy supply might
be needed. It may be associated with supply of energy for
Na+ /K+ pumping which is responsible for a significant
part of energy consumption in the CNS (Mata et al., 1980).
Na+ /K+ ATPase activity occurs in both astrocytes and neu-
rones. The breakdown of glutamate to glutamine is also
energy expensive (Hertz and Fillenz, 1999) and important
for memory consolidation (Gibbs et al., 1996). Stimulation
of ␤2 -ARs probably increases vasodilation and so increases
cerebral blood flow and hence the supply of glucose and
other nutrients to both neurones and astrocytes.
12.1.2. Physiological consequences
The physiological consequences of activation of ARs in
memory consolidation could be associated with the ability of
␤2 -ARs to enhance signal-to-noise ratio of the sodium pump
(Jeffrey and Gibbs, 1976)—which could be a mechanism
for marking neurones for subsequent changes required for
memory storage (Mark and Watts, 1971; Gibbs, 1976; Gibbs
and Ng, 1976a). If ␣1 -ARs are recruited at times of high
stress levels this could lead to a reduction in signal-to-noise
ratio, possibly caused by release of glutamate, and
this may account for memory loss in highly stressful
situations.
12.1.3. Psychological consequences
The psychological consequences of activation of ␤1 -ARs
may relate to arousal and attention processes in the basal
ganglia (LPO) important for STM in the association cortex
(IMHV), whereas activation of ␣2 -ARs in the basal ganglia
may be related to reinforcement and consequent consolida-
tion of labile memory into a more permanent form in the
association cortex (IMHV).
 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
12.2. Interactions of noradrenaline with hormones and
other neurotransmitter systems
Hormones may influence memory processes by modulat-
ing the action of noradrenaline, either directly or indirectly.
For example, arginine vasopressin (De Wied et al., 1984)
induced neuromodulation and cAMP accumulation in the
hippocampus involves ␤-ARs (Brinton and McEwan, 1989).
In the chick, vasopressin and vasotocin (the avian analogue)
modulate memory (Gibbs and Ng, 1986; Crowe et al.,
1990; Gibbs et al., 1991). Glucocorticoid enhancement of
memory involves ␤-ARs (Quirarte et al., 1997; Roozendaal
et al., 1999) and corticosterone modulates memory in the
chick (de Vaus et al., 1980; Gibbs and Ng, 1986). The ac-
tion of corticosterone on memory consolidation in the chick
also appears to be related to the action of noradrenaline
on ARs (unpublished observation). There is the possibil-
ity that any noxious event which produces an increase in
noradrenaline levels immediately after training will lead to
memory consolidation (Ettenberg et al., 1983).
Many neurotransmitter systems have been implicated in
memory formation including nitric oxide (Yamada et al.,
1995; Rickard et al., 1998), serotonin (Meneses and Hong,
1999), acetylcholine (Blokland, 1996) and opioids (Liang
et al., 1983; Introini-Collison and Baratti, 1986; Flood et al.,
1987; Patterson and Alvarado, 1989; Lee and Rosenzweig,
1991; McGaugh and Cahill, 1997; Freeman and Young,
2000). Activation of many of these systems may involve
noradrenaline release. Noradrenaline has been shown to
interact with serotonin release in the raphe nucleus (e.g.
Adell and Artigas, 1999; Kalsner and Abdali, 2001) and
interactions between 5-HT and noradrenergic systems have
been suggested (van Bockstaele, 2000). Opiates and opioid
peptides impair, and opiate antagonists enhance memory
retention, with the latter effect possibly resulting from re-
lease of brain noradrenaline (Arnsten et al., 1981; Gallagher
et al., 1985). Nitric oxide induces noradrenaline release in
the hippocampus (Ohkuma and Katsura, 2001) and is able
to inhibit the function of monoamine transporters (Kiss and
Vizi, 2001) leading to an increase in extracellular nora-
drenaline. Because monoamines can inhibit the release of
glutamate, this NO-mediated interaction might serve as a
negative feedback loop (Kiss and Vizi, 2001).
There are therefore, many interactions between nora-
drenaline with other transmitters that could contribute to
the effects of noradrenaline on memory storage.
It seems clear that noradrenergic modulation of acqui-
sition and consolidation is as important as the intrinsic
pathways using primary neurotransmitters in the formation
of memory. Glutamate and GABA, in particular, can be re-
garded as playing an intrinsic role, as transmitters involved
in the processing of information in neuronal pathways and
networks within and between the neuronal centers involved
in memory. If the activity of either is inhibited, memory pro-
cessing stops. Noradrenaline, on the other hand, is involved
in the modulation of memory formation, and determines the
385
extent to which an event is remembered. The influence is
likely to come from areas such as the amygdala, prefrontal
cortex, etc. and may be determined from information al-
ready stored on the basis of past experience or from innate
‘information’ which is programmed during development
(imprinting or preparedness). In any learning experience,
there will normally be fluctuations of endogenous levels
of noradrenaline release on top of normal phasic or tonic
alterations. So although memory formation is prevented
by inhibiting glutamate or GABA transmission and this is
the ‘essential’ component of memory formation, we would
argue that noradrenergic modulation is equally important.
12.3. Noradrenaline and cognitive diseases
Noradrenergic changes have been implicated in a number
of neurodegenerative diseases, including cognitive decline
in old age (Sternberg et al., 1985b; Scarpace and Abrass,
1988; Mabry et al., 1995; Shores et al., 1999; Stemmelin
et al., 2000; Ishida et al., 2001). There is an abundance of
evidence that along with cholinergic atrophy, monoamines
are reduced in Alzheimer’s disease and it is possible that
enhancement of monoaminergic functions has beneficial
effects on behavior and cortical activity (Hertz, 1989;
Dringenberg, 2000). Noradrenaline is also implicated in
anxiety, fear (Sullivan et al., 1999) and depression (Zhu
et al., 1999).
Many of the cognitive neurodevelopmental disorders
such as attention-deficit hyperactivity disorder, schizophre-
nia, autism, and depression (Arnsten, 1998a; Russell et al.,
2000; Bradshaw, 2001) have neurotransmitter disturbances,
including noradrenaline imbalance.
Most drugs that enhance memory show a lack of speci-
ficity in terms of types of modulators and tasks or the
‘emotional content’ of the experiences and there has been
a tendency to assign the two to different brain structures
(Gold, 1995). Lipp and Wolfer (1998) question whether
cognition should not encompass all aspects of adaptive be-
havior, such as emotion, learning, memory and flexibility?
Noradrenaline has the potential to enhance memory forma-
tion independent of the type of learning task, whether it is
appetitive or aversive in the chick as well as in mammals.
13. General conclusion
Although in this review experiments with the single-trial
learning paradigm in the chick have been used to illustrate
the importance of noradrenergic involvement in memory
storage, it is likely that the principles will apply equally
to mammalian memory storage. A major advantage of the
chick paradigm is that there is little innate information re-
garding colored beads to complicate behavioral outcomes.
On the basis of existing knowledge from mammalian
systems, it is likely that the noradrenergic influences on
memory formation in the chick will hold for mammals.
386 M.E. Gibbs, R.J. Summers / Progress in Neurobiology 67 (2002) 345–391
There has been to date few direct comparisons made be-
tween paradigms in chick and mammal, mainly due to a
scarcity of one-trial learning paradigms in mammals. Where
single-trial paradigms do exist for mammals, the time course
has not been investigated in sufficient detail to enable the
distinction between the stages of memory formation to be
revealed. Passive avoidance models in rodents that involve
footshock may not be sensitive enough to reveal the stages,
although there are indications that the stages may be the
same and of similar durations.
In neural terms cognition has to be considered as an
interaction between posterior multimodal association areas
and the higher order areas such as the prefrontal cortex, hip-
pocampus and amygdala. Memory processing will probably
occur in all of these sites. For control of memory processing
the interplay between these areas needs to be controlled. As
Lipp and Wolfer (1998) suggest ‘the most likely candidate
is the reticular formation (including the LoC) of the rostral
brain stem, which controls cortical interplay through both
ascending control systems and the thalamic nuclei project-
ing to the limbic and associative cortex.’ This review of
the actions of noradrenaline in one learning task in the one
species, suggests that noradrenaline is a likely transmitter
to perform this function.
Noradrenaline, rather than playing a ubiquitous role in
memory formation and consolidation, has well-defined roles
in STM and ITM. These roles vary according to the location
in the brain and the in the memory processing sequence. We
have been able to differentiate between roles for different
AR subtypes responsible for the selectivity of action of no-
radrenaline. The major role of noradrenaline with respect to
memory formation may be in the orchestration of various
activities in the brain related to the formation of memory.
Acknowledgements
This review was written while the authors were in receipt
of a grant from the National Health and Medical Research
Council of Australia. They would like to acknowledge the
input of Ms. Emily Camm and critical comments on the
manuscript by Professor U. Proske and A/Professor G.
Jenkin. Many of the earlier cited papers are the result of a
long-term collaboration between M.G. and Professor K.T.
Ng. Figures from Gibbs and Summers (2000, 2001a,b)
reproduced with permission of the publishers.
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