www.elsevier.com/locate/pharmbiochembeh
Abstract
The aversive aspects of withdrawal from chronic nicotine exposure are thought to be an important motivational factor contributing to the
maintenance of the tobacco habit in human smokers. Much emphasis has been placed on delineating the underlying neurobiological
mechanisms mediating different components of the nicotine withdrawal syndrome. Recent studies have shown that both central and
peripheral populations of nicotinic acetylcholine receptors (nAChRs) are involved in mediating somatic signs of nicotine withdrawal as
measured by the rodent nicotine abstinence scale. However, only central populations of nAChRs are involved in mediating affective aspects
of nicotine withdrawal, as measured by elevations in brain-stimulation reward thresholds and conditioned place aversion. Nicotine interacts
with several neurotransmitter systems, including acetylcholine, dopamine, opioid peptides, serotonin, and glutamate systems. Evidence so far
suggests that these neurotransmitters play a role in nicotine dependence and withdrawal processes. The available evidence also suggests that
different underlying neurochemical deficits mediate somatic and affective components of nicotine withdrawal. The aim of the present review
is to discuss preclinical findings concerning the neuroanatomical and neurochemical substrates involved in these different aspects of nicotine
withdrawal. D 2001 Elsevier Science Inc. All rights reserved.
Keywords: Nicotine; Drug withdrawal; Conditioned place aversion; Intracranial self-stimulation; Reward; Somatic signs; Depression; Acetylcholine;
Dopamine; Opioid; Serotonin; Glutamate
1. Introduction
The burden of disease and negative economic impact of
tobacco addiction on society is considerable. It has been
projected that by 2020 tobacco will become the largest
single health problem worldwide, causing approximately
8.4 million deaths annually (Murray and Lopez, 1997).
Furthermore, the World Bank estimates that in high-income
countries, smoking-related healthcare accounts for 6 15%
of all annual healthcare costs. In fact, approximately 1.5
billion was spent between 1996 1997 on the care and
treatment of patients suffering from tobacco-related diseases
in England alone (Parrott et al., 1998). Therefore, there is
much incentive to develop interventions designed to reduce
and prevent tobacco use. To achieve this goal, it is necessary
to understand the mechanisms by which tobacco addiction
occurs. Evidence suggests that nicotine, which acts at
neuronal nicotinic acetylcholine receptors (nAChRs), is
2. Neuronal nAChRs
Nicotinic receptors are expressed on mature skeletal
muscle, in autonomic ganglia and within the central nervous
system (CNS) (Holladay et al., 1997). Not surprisingly, most
interest in the behavioral actions of nicotine has focused on
the role of nAChRs located within the CNS. Neuronal
nAChRs are members of the superfamily of ligand-gated
ion channels that include g-aminobutyric acidA (GABAA),
GABAC, glycine, and serotonin3 (5-HT3) receptors that are
0091-3057/01/$ see front matter D 2001 Elsevier Science Inc. All rights reserved.
PII: S 0 0 9 1 - 3 0 5 7 ( 0 1 ) 0 0 6 5 1 - 7
532
fields and have fundamentally different physiological characteristics (e.g., Takahata and Moghaddam, 2000). It is
possible that the complex expression patterns of nAChRs
within the VTA may represent differential expression of
nAChR subtypes on different populations of dopamine
neurons, which may contribute to the heterogeneity of these
neurons. Such investigations offer the intriguing possibility
that different nAChR subtypes involved in various aspects
of nicotine reward, dependence, and withdrawal processes
may eventually be identified and targeted.
The function of nAChRs within the brain also has been
investigated. Nicotinic receptors within the CNS are situated
mainly on presynaptic terminals (Wonnacott, 1997) but also
are found at somatodendritic, axonal, and postsynaptic locations (for review see Sargent, 1993). It has been proposed that
the exclusive or predominant role of nAChRs in the CNS is
the modulation of neurotransmitter release (Wonnacott,
1997). Accordingly, by an action at nAChRs, nicotine has
been shown to stimulate the release of most neurotransmitters
in regions throughout the brain (Araujo et al., 1988; Toide
and Arima, 1989; McGehee et al., 1995; McGehee and Role,
1995; Gray et al., 1996; Role and Berg, 1996; Wilkie et al.,
1996; Albuquerque et al., 1997; Alkondon et al., 1997;
Kenny et al., 2000a; Grady et al., 2001). Therefore, as
discussed in detail below, it is likely that various neurotransmitter systems are involved in the adaptations that occur
in response to chronic nicotine exposure that give rise to
dependence and withdrawal responses.
533
Fig. 1. During nicotine withdrawal rats exhibit increased number of somatic signs of withdrawal. (A) Somatic withdrawal signs in rats undergoing spontaneous
nicotine withdrawal after removal of osmotic minipump delivering nicotine (3.16 mg/kg/day free base, 7 days) and in vehicle-treated control rats. (B) Effect of
mecamylamine (sc) on somatic signs in nicotine- and vehicle-treated rats. (C) Effect of dihydro-b-erythroidine (DHbE, sc) on somatic signs in nicotine- and
vehicle-treated rats. (D) Effect of methyllycaconitine (MLA) (sc) on somatic signs in nicotine- and vehicle-treated rats. (E) Effect of chlorisondamine (sc) on
somatic signs in nicotine- and vehicle-treated rats. (F) Effect of chlorisondamine (icv) on somatic signs in nicotine- and vehicle-treated rats. Asterisks indicate
statistically significant differences between nicotine- and saline-treated rats ( * P < .05, ** P < .01). Hash symbols indicate statistically significant difference in
overall somatic withdrawal signs compared to 0.0 mg/kg DHbE ( # P < .05). All data are expressed as mean ( S.E.M.) somatic signs of withdrawal at each time
point or antagonist dose. Reproduced with permission from Epping-Jordan et al. (1998) and Watkins et al. (2000b).
534
Table 1
Minimal dose (mg/kg) of nicotinic and opioid receptor antagonists that precipitated statistically significant increases in somatic abstinence signs, elevated brain
reward thresholds or induced conditioned place aversions in nicotine-dependent rats compared to saline-treated controls
Somatic signs
Reward thresholds
a
Indicates that these receptor antagonists either had no effect or did not induce differential effects on somatic signs of withdrawal, reward threshold
elevations, or conditioned place aversions at any dose tested (data taken from Epping-Jordan et al., 1998; Watkins et al., 2000b; Markou and Paterson, in press).
is possible that administration of a higher dose of mecamylamine which would block an even greater number of
nAChRs may precipitate withdrawal signs in nicotinedependent smokers.
535
place aversion paradigm. Clinical and preclinical observations have demonstrated that negative affective states
experienced during drug withdrawal can become associated
with previously neutral stimuli and that these conditioned
stimuli gain motivational significance. That is, drugdependent rats are treated with an antagonist to precipitate
withdrawal and are confined to one compartment of the
conditioned place aversion apparatus. On a different day,
the same subjects are confined in a different compartment
following a saline injection. This procedure leads to an
association of the withdrawal-paired compartment with a
negative affective state. Thus, during subsequent exposures
to the apparatus, subjects tend to avoid the compartment
associated with the withdrawal effects. For example, precipitated opiate withdrawal in rats has been shown to
produce an aversive motivational state that becomes associated with environmental cues and leads to a conditioned
place aversion (Hand et al., 1988; Stinus et al., 1990;
Schulteis et al., 1994, 1998; Spanagel et al., 1994). These
conditioned effects appear to play a significant role in
nicotine dependence (Butschky et al., 1995; Baldinger
et al., 1995). The effect of antagonist-precipitated nicotine
withdrawal on conditioned place aversion also has been
recently investigated (Table 1). DHbE produced a conditioned place aversion after systemic administration in rats
chronically treated with nicotine (Ise et al., 2000; Watkins et
al., 2000b; Suzuki et al., 1996, 1997, 1999) (Fig. 3). This
conditioned place aversion was demonstrated by a significant reduction in the time spent in the compartment paired
with DHbE administration in nicotine-dependent but not
control rats (Watkins et al., 2000b). However, a relatively
high dose of DHbE (10 mg/kg) (Watkins et al., 2000b) was
required to produce this conditioned place aversion compared to the low dose (2 4 mg/kg) (Epping-Jordan et al.,
1998; Watkins et al., 2000a) required to precipitate elevations in brain reward thresholds (see Table 1). Watkins et al.
(2000b) reported that mecamylamine (0.5 6 mg/kg) did not
produce a conditioned place aversion (Fig. 3) but did
precipitate elevations in brain reward function (Fig. 2) in
nicotine-dependent compared to control rats. These observations taken together suggest that a dissociation may exist
in the underlying mechanisms mediating conditioned place
aversions compared to those mediating elevations in brain
reward thresholds observed during nicotine withdrawal.
More specifically, the fact that relatively low does of
mecamylamine (0.57 mg/kg) or DHbE (2 mg/kg) (see
Table 1) induced statistically significant threshold elevations in nicotine-dependent rats, whereas a much higher
dose of DHbE (10 mg/kg) was required to produce a
conditioned place aversion, with no differential effects of
even high mecamylamine doses (4 6 mg/kg) in nicotineversus saline-treated rats, indicates possible differences in
the neurobiological substrates mediating various aspects of
nicotine withdrawal. Interestingly, Suzuki et al. (1997)
found that mecamylamine (1 mg/kg) did produce a conditioned place aversion in nicotine-dependent rats (Suzuki
536
Fig. 2. Nicotine withdrawal in rats is associated with elevations in brain reward thresholds. (A) Percentage of baseline reward thresholds in rats tested 2 152 h
after removal of osmotic minipump delivering nicotine (3.16 mg/kg/day free base, 7 days). (B) Percentage of baseline reward thresholds in nicotine- and
vehicle-treated rats after mecamylamine (sc) administration. (C) Percentage of baseline reward thresholds in nicotine- and vehicle-treated rats after dihydrob-erythroidine (DHbE, sc) administration. (D) Percentage of baseline reward thresholds in nicotine- and vehicle-treated rats after administration of
methyllycaconitine (MLA) (sc). (E) Percentage of baseline reward thresholds in nicotine- and vehicle-treated rats after administration of chlorisondamine (sc).
(F) Percentage of baseline reward thresholds in nicotine- and vehicle-treated rats after administration of chlorisondamine (icv). Asterisks indicate statistically
significant differences between nicotine- and saline-treated rats ( * P < .05, ** P < .01). Hash symbols indicate statistically significant difference in overall
somatic withdrawal signs compared to 0.0 mg/kg chlorisondamine ( # P < .05). All data are expressed as mean ( S.E.M.) overall somatic withdrawal signs at
each time point or antagonist dose. Reproduced with permission from Epping-Jordan et al. (1998) and Watkins et al. (2000b).
Fig. 3. Conditioned place aversion induced by sc administration of dihydrob-erythroidine, mecamylamine, or naloxone in nicotine- (3.16 mg/kg/day
free base) and vehicle-treated rats. All data are presented as mean
( S.E.M.) difference in time spent in the antagonist-paired compartment
before conditioning versus after conditioning. Asterisks indicate statistically
significant differences between the time spent in the antagonist-paired
compartment compared before conditioning compared with after conditioning ( * P < .05, ** P < .01). Reproduced with permission from Watkins
et al. (2000b).
and Lu, 1969), precipitated few withdrawal signs in nicotine-dependent rats (Malin et al., 1997). Conversely, direct
intracerebral hexamethonium injection precipitated somatic
signs of withdrawal in nicotine-dependent rats (Malin et al.,
1997). It was therefore concluded that somatic withdrawal
signs are directly mediated by central but not peripheral
populations of nAChRs (Malin et al., 1997). More recently,
Watkins et al. (2000b) demonstrated that chlorisondamine at
doses (0.1 1 mg/kg) that do not readily cross the blood
537
brain barrier (Gosling and Lu, 1969) precipitated significantly more somatic signs of withdrawal in nicotine-treated
rats compared to saline-treated rats (Table 1). Similarly,
Hildebrand et al. (1997) also showed that systemic administration of chlorisondamine (1 mg/kg) precipitated somatic
withdrawal signs in nicotine-treated rats. Moreover, administration of either nicotine or the peripherally active nAChR
agonist tetramethylammonium reversed somatic withdrawal
signs (Hildebrand et al., 1997). Therefore, in contrast with
the findings of Malin et al. (1997), these observations
suggest that nAChRs located peripherally contribute to the
expression of somatic signs in rats undergoing nicotine
withdrawal. This discrepancy may be explained in part
by the fact that hexamethonium is not very effective at
blocking nAChRs compared to other nAChR antagonists
(Marks et al., 1993) such as chlorisondamine, particularly
at peripheral ganglia (Abdel-Rahman, 1989; Santajuliana
et al., 1996). nAChRs located within the brain also likely
play a role in mediating somatic withdrawal signs. For
example, direct intraventral tegmental area injection of
mecamylamine (Hildebrand et al., 1999) or icv administration of chlorisondamine (Watkins et al., 2000b; Fig. 1)
both precipitated somatic withdrawal signs. Overall, it
appears that centrally and peripherally located populations
of nAChRs are involved in mediating somatic signs of
nicotine withdrawal.
It is likely that centrally located populations of nAChRs
are exclusively involved in mediating affective aspects of
nicotine withdrawal. Systemic administration of the neuronal nAChR antagonist, DHbE, which selectively blocks
centrally located high affinity neuronal nAChRs (Harvey
et al., 1996), precipitated elevations in brain reward thresholds (Epping-Jordan et al., 1998; Fig. 2) and produced a
conditioned place aversion (Watkins et al., 2000b; Fig. 3) in
nicotine-treated rats (Table 1). However, DHbE produced
only modest increases, and only at a high dose (4 mg/kg), in
the number of somatic signs with no differences between
nicotine-dependent and control rats (Epping-Jordan et al.,
1998; Fig. 1), suggesting that nicotine-dependent animals
are not more sensitive than saline-treated controls to the
increases in somatic signs of withdrawal induced by DHbE
(Table 1). Further, systemic administration of doses of
chlorisondamine (0.1 1 mg/kg) that do not penetrate the
blood brain barrier had no effect on brain reward thresholds (Epping-Jordan et al., 1998; Watkins et al., 2000b)
whereas direct icv administration of chlorisondamine precipitated elevations in reward thresholds (Fig. 2). Finally,
systemic administration of hexamethonium (1 3 mg/kg) at
doses that do not penetrate the blood brain barrier had no
effect on conditioned place aversion in rats chronically
treated with nicotine (Ise et al., 2000). Overall, this pattern
of results suggests that unlike somatic withdrawal signs that
are peripherally and centrally mediated, affective aspects of
nicotine withdrawal (conditioned place aversion and elevations in brain reward thresholds) are mediated exclusively by
central populations of nAChRs. Furthermore, observations
538
demonstrating that somatic withdrawal signs can be precipitated in the absence of affective signs and vice versa supports
the notion that a dissociation exists in the underlying
mechanisms mediating somatic and affective aspects of
nicotine withdrawal.
539
540
541
542
9. Discussion
Evidence so far suggests that the negative affective
aspects of nicotine withdrawal, which appear to be mediated exclusively by central populations of nAChRs, are
regulated by a number of different neurotransmitter systems. For example, deficits in serotonergic neurotransmission are likely to be involved in mediating elevations in
brain reward thresholds (Harrison et al., 2001) whereas
decreased opioid receptor activity is likely to be involved
in the conditioned aversive motivational states associated
with nicotine withdrawal (Watkins et al., 2000b). Although
it is clear that both central and peripheral populations of
nAChRs are involved in mediating somatic aspects of
nicotine withdrawal, it is unclear what other neurotransmitter systems besides the cholinergic system are also
involved. One strong candidate is the noradrenergic system.
There is now a considerable amount of evidence suggesting
that noradrenaline plays a major role in mediating somatic
signs in rats undergoing opiate withdrawal (Delfs et al.,
2000; Maldonado, 1997). Moreover, clonidine, which acts
to decrease noradrenergic neurotransmission, has shown
efficacy in smoking cessation trials (for review see Gourlay
et al., 2000). Therefore, it is possible that noradrenaline may
play a role in mediating somatic signs in rats undergoing
nicotine withdrawal, although further studies are required to
address this possibility.
In addition to the classical neurotransmitters such as
serotonin and glutamate discussed in the present review, it
is likely that neuropeptides other than endogenous opiates
play a role in nicotine dependence and withdrawal. For
example, the cholecystokinin-B (CCK-B) receptor antagonist LY288513 reversed the enhanced startle response in rats
undergoing nicotine withdrawal (Rasmussen et al., 1996).
Interestingly, withdrawal from various drugs of abuse,
including ethanol (Pich et al., 1995), cocaine (Richter and
Weiss, 1999), opiates (Milanes et al., 1998), and even
cannabis (Rodriguez de Fonseca et al., 1997) has been shown
to increase the release of corticotropin-releasing factor
(CRF). CRF receptor antagonists alleviated symptoms of
withdrawal associated with these drugs (Baldwin et al., 1991;
Rassnick et al., 1993; Menzaghi et al., 1994; Heinrichs et al.,
1995; Basso et al., 1999; Lu et al., 2000). Furthermore,
similar to nicotine withdrawal, CRF and urocortin, a CRF
receptor agonist, elevated brain-stimulation reward thresholds in rats (Macey et al., 2000). Taken together, these
observations suggest that increased CRF also may play a
role in the aversive aspects of nicotine withdrawal. Interestingly, Heinrichs et al. (1996) and Sarnyai et al. (2001) have
reported that the CRF-binding protein ligand inhibitor CRF
(6 33) that acts to increase levels of free CRF in the brain,
suppressed the increase in weight gain observed in rats
undergoing nicotine withdrawal, but had no effect in nicotine nave rats. This observation suggests that the activity
of CRF-binding protein may increase during nicotine withdrawal in order to compensate for an increase in the levels
of free CRF. Another neuropeptide that potentially could
play a role in nicotine withdrawal is substance P. This
neuropeptide acts at the neurokinin-1 (NK-1) receptor.
Blockade or genetic disruption of this receptor has been
shown to have anxiolytic (File, 1997, 2000; Santarelli et al.,
2001) and antidepressant (Kramer et al., 1998) effects. NK-1
receptor antagonists significantly decreased naloxoneprecipitated withdrawal behaviors in opiate-dependent rats
(Maldonado et al., 1993). Similarly, there was a significant
reduction in opiate withdrawal in mice with genetic deletion
of the NK-1 receptor (Murtra et al., 2000). Because there is
such a close interaction between nicotinic and opioid
receptors in mediating nicotine dependence, these observations suggest that substance P also may play a role in
nicotine withdrawal.
As evidenced by the content of the present review, most
investigations into the mechanisms underlying nicotine
withdrawal have focused on particular neurotransmitter
systems or receptors. However, it is likely that many of
the neurochemical effects produced by chronic nicotine
exposure converge at common molecular and cellular targets to give rise to the long-lasting changes in brain
structure and function that ultimately lead to dependence.
Therefore, investigation of molecular alterations associated
with nicotine dependence and withdrawal offers a promising
research target. There are a number of candidate molecular
substrates that might play a role in mediating cellular
adaptations to chronic nicotine exposure. One possibility
is that chronic nicotine treatment may alter the expression of
specialized intracellular signaling proteins like cyclic AMP
response element-DNA-binding protein (CREB) and c-fos
543
Acknowledgments
The authors would like to thank Dr. Cecile Spielewoy for
her helpful comments and suggestions and Mike Arends for
editorial assistance. This work was supported by NIDA
grant DA11946, Tobacco-Related Disease Research Program grant 7RT-0004, and a Novartis Research Grant to
AM. This is publication 14181-NP from The Scripps
Research Institute.
544
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