735750, 1998
1998 Elsevier Science Ltd. All rights reserved
Printed in Great Britain
0149-7634/98 $32.00 + .00
Pergamon
PII: S0149-7634(98)00002-5
A.I. Virtanen Institute, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland
b
Orion Corporation, OrionPharma, P.O. Box 425, FIN-20101 Turku, Finland
c
Department of Neuroscience and Neurology, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland
. Systemic
NIITTYKOSKI M., R. LAPPALAINEN, J. JOLKKONEN, A. HAAPALINNA, P. RIEKKINEN Sr and J. SIRVIO
administration of atipamezole, a selective antagonist of alpha-2 adrenoceptors, facilitates behavioural activity but does not influence
short-term or long-term memory in trimethyltin-intoxicated and control rats. NEUROSCI BIOBEHAV REV 22(6) 735750, 1998.
The present study used trimethyltin (TMT)-intoxicated rats as a model for the behavioural syndrome seen after neuronal damage to the
limbic system. Behavioural assessments indicated increased locomotor activity and reduced number of groomings in an open-arena task
in TMT-intoxicated (6.6 mg/kg as a free base) rats, as has been found previously. A novel finding was the severe deficit in swimming to a
visible platform in the water maze task, with reduced swimming speed at the beginning of the training period. During the reacquisition
phase of a radial arm maze task, TMT-intoxicated rats made more short-term and long-term memory errors, and their behavioural
activity was increased in comparison with controls. The administration of atipamezole (300 mg/kg), a selective antagonist of a 2adrenoceptors, enhanced locomotor activity compared to saline-treated rats, but these effects did not differ between the TMT group and
their controls. Atipamezole did not enhance short-term or long-term memory in either TMT or control groups. Taken together, the
present data indicate that TMT intoxication is a model for global dementia rather than for a specific loss of relational memory. Previous
studies on the neurochemical effects of TMT and the alleviation or prevention of neurotoxicity of TMT are reviewed. 1998 Elsevier
Science Ltd. All rights reserved
Alzheimers disease
a 2-adrenoceptors
Hippocampus
Hyperactivity
Memory
Rat
Schizophrenia
Trimethyltin
experimental animals (30). In rats, TMT induces the degeneration of pyramidal neurons in the hippocampus and
cortical areas (pyriform cortex, entorhinal cortex, subiculum) connected to the hippocampus, but there is also
neuronal loss in the association areas (7,13,19,20). Furthermore, behavioural studies have shown increased locomotor
activity, disruption in self-grooming and learning deficits in
TMT-intoxicated rats (2,18,22,31,41,58,93,103,123). TMT
intoxication impairs the acquisition of water maze and Biel
maze (water avoidance) tasks as well as HebbWilliams
maze and radial arm maze performance (2,31,41,48,72
74,93,103,113,123). In addition, TMT intoxication produces deficits in passive avoidance retention, but not in
the acquisition of the passive avoidance response
INTRODUCTION
THE HIPPOCAMPUS has reciprocal, multisynaptic connections with the cerebral cortex, and is considered to be
involved in certain forms of associative learning and
memory, especially the encoding phase of memory processing (101). In addition, the hippocampus and its output
area, the subiculum, send projections to the nucleus accumbens, which may be important in sensori-motor control
(63,119). Lesions of hippocampal formation and associated
dysfunctions are known to occur, e.g., in Alzheimers
disease (AD) (47,87,94,99,125) and schizophrenia (4,81).
Intoxication with trimethyltin (TMT) leads to profound
behavioural and cognitive deficits in both humans (33) and
* To whom correspondence should be addressed. Tel.: 358-(0)17-162086; fax: 358-(0)17-163030; e-mail: jouni.sirvio@uku.fi
735
736
NIITTYKOSKI ET AL.
TABLE 1
The neurochemical effects of TMT
Rat strain
Reference
LAC:P (m)
F344 (m)
WI
LAC:P (m)
WI (m)
WI (m)
LAC:P (m)
F344 (m)
SD (m)
LE (m f)
(12)
(117)
(49)
(12)
(66)
(66)
(12)
(117)
(31)
(55)
LAC:P (m)
WI
LE (m f)
WI (m)
LE (m)
SD (m)
LE (m)
WI (m)
LE (m)
LE (m)
LE (m)
LE (m)
SD (m)
SD (m)
F344 (m)
SD (m)
LE (m)
SD (m)
SD (m)
LAC:P (m)
F344 (m)
SD (m)
SD (m)
LE (m)
LE (m)
LAC:P (m)
SD (m)
SD (m)
LE (m f)
SD (m)
SD (m)
LE (m)
F344 (m)
LE (m)
SD (m)
LE (m)
SD (m)
LE (m f)
LE (m)
LE (m)
LE (m)
(12)
(49)
(55)
(41)
(120)
(48)
(15)
(66)
(17)
(16)
(16)
(16)
(31)
(71)
(117)
(3)
(26)
(31)
(3)
(12)
(117)
(3)
(31)
(26)
(25)
(12)
(3)
(31)
(55)
(3)
(31)
(59)
(117)
(26)
(3)
(25)
(31)
(55)
(26)
(25)
(26)
Abbreviations: increased; decreased; no effect; # histological staining; autoradiographical method; ACh acetylcholine; AChE
acetylcholinesterase; am amygdala; brst brain stem; cd caudate; cer cerebellum; Ch choline; ChAT choline acetyltransferase; d day; DA
dopamine; DG dentate gyrus; DOPAC 3,4-dihydroxyphenylacetic acid; ent entorhinal cortex; f female; frctx frontal cortex; F344 Fischer-344;
GABA g-aminobutyric acid; GLU glutamate; hip hippocampus; 5-HIAA 5-hydroxyindoleacetic acid; 5-HT serotonin; hyp hypothalamus; i.g.
intragastrically; i.p. intaperitoneally; LE LongEvans; m male; M muscarinic; midbr midbrain; NA noradrenaline; nac nucleus
accumbens; olf olfactory tubercle; p.o. per os; py pyriform cortex; s.c. subcutaneosly; SD SpragueDawley; sep septum; st striatum; sub
subiculum; w week; WI Wistar.
737
738
NIITTYKOSKI ET AL.
Animals
Male Bkl Wistar rats (National Animal Center, University of Kuopio, n 40) were used (3 months old at the
beginning of the experiment). Animals were housed and
maintained on a 12:12 h lightdark cycle, and the room
was controlled for temperature (20 2C) and humidity (55
10%). All testing was conducted during the light part of
the cycle. Except for two rats used for weight controls, the
rats (n 38) were housed singly, and their weight was
reduced by gradually decreasing their amount of daily food
739
FIG. 1. Schedule of the study. The numbers represent the days from TMT administration.
740
NIITTYKOSKI ET AL.
FIG. 2. The performance of saline-treated control (n 16) and TMT-intoxicated (n 15) rats in the open arena task assessed 31 days after TMT
administration. The results on the ambulation, rearings and groomings are expressed as group means SEM for each interday trial.
1
The water maze task was not used as an outcome measure, because
atipamezole reduces the speed of swimming; atipamezole ( 300 mg/kg)
treated rats put into a water tank float for some time ( 10 s) before they
begin to swim (our unpublished findings).
Histology
Some rats from each group (two from salinesaline,
one from salineatipamezole, two from TMTsaline, one
from TMTatipamezole) were processed for histology.
The rats were anaesthetized with MEBUNAT (sodium
pentobarbital, 100 mg/kg) before perfusion. They were
transcardially perfused with 0.9% saline followed by fixative containing 4% paraformaldehyde, 0.05% glutaraldehyde and 0.2% picric acid in 0.1 m phosphate buffer
(pH 7.4). After perfusion, the brains were removed from
the skull, postfixed in the perfusion fixative for 2 h and
placed in 20% glycerol in 0.02 m potassium phosphate
buffered saline (pH 7.4) for 22 h. Then the brains were
frozen on dry ice.
Frozen sections (30 mm) were cut with a sliding microtome in the coronal plane and stored in 10% formalin in
0.1 m phosphate buffer (pH 7.4). The overall neuronal
damage caused by TMT was estimated from Nissl stained
sections. In addition, the cortical shrinkage was measured
using an image analysis system (Imaging Research Inc.)
combined with a DAGE MTI CCD-72 series camera
(DAGE.MTI) at two anteroposterior levels: AP 1.60 mm
and 3.80 mm from the Bregma (79).
Statistical analysis of data
The group effect (controls vs TMT-intoxicated rats),
treatment effect (saline vs atipamezole), testing effect
(three 3 min periods) and their interactions in the data on
the open-arena task (distance, number of rearings and
groomings) were analysed using ANOVA for repeated
measurements. The group effect in the number of fecal
boli was analysed using ANOVA. The group effect, testing
effect (training days) and their interactions in the data on
water maze performance were analysed with ANOVA for
repeated measurements. The group effect in the data on
the retention of a radial arm maze task was also analysed
using ANOVA. The group effect, treatment effect, testing
effect (training blocks) and their interactions in the data
on reacquisition of a radial arm maze task were analysed
using ANOVA for repeated measurements. The data
from two or three consecutive days were combined to
blocks of trials. The feeding data were analysed with
ANOVA.
741
FIG. 3. The performance of saline-treated control and TMT-intoxicated rats in the water maze task using a visible platform in a constant position (A) and
variable position (B). The group means SEM for escape latency and distance as well as swimming speed are presented for each training day.
RESULTS
742
NIITTYKOSKI ET AL.
FIG. 4. The effects of saline and atipamezole (300 mg/kg) treatments on the performance of TMT-treated rats and their controls in the radial arm maze task.
The results indicate the group means SEM across the trial blocks for the reference memory errors (the number of the entries to non-baited arms), working
memory errors (the numbers of re-entries to either baited or non-baited arms) and locomotor activity (the number of arm entries in a minute). Groups: TMT
atipamezole (TMT/ATI, n 7), TMTsaline (TMT/sal, n 7), salineatipamezole (sal/ATI, n 8), salinesaline (sal/sal, n 8).
743
FIG. 5. The effects of saline and atipamezole (300 mg/kg) treatments on the performance of TMT-treated rats and their controls in the open-arena task. The
results show the group means SEM on the length of path, the number of rearings, the number of groomings and the number of fecal boli.
Histology
The gross inspection of Nissl-stained sections revealed a
severe neuronal loss following systemic injection of TMTchloride (8 mg/kg) at 112 days after intoxication. There was
some selectivity in the neuronal loss. The pyramidal
neurons in the hippocampal CA1 and CA3 area were
particularly vulnerable (Fig. 7D). The neuronal loss was
Toxicity of TMT
In the present study, approximately 30% of rats exposed
to TMT died within 22 days despite receiving postoperative
care. Dyer et al. (30) described mortality after TMT and
noted that heavier animals were more susceptible to TMT
toxicity than leaner animals; for example, 10% mortality
FIG. 6. The amount of food consumed in 24 h ( SEM) in the baseline conditions, 8 days after TMT administration, and 98 days after TMT administration
following the last testing day in a radial arm maze. The wctrl group includes two weight control rats.
744
NIITTYKOSKI ET AL.
FIG. 7. Photomicrographs from Nissl-stained sections of a control (salinesaline-treated) rat (A and C) and a TMT-intoxicated, saline-treated rat (B and D) at
two rostrocaudal levels. Note the severe neuronal loss in the hippocampus and cortical areas and enlargement of ventricles in the TMT-intoxicated rat in the
posterior level (D). Magnification: 12.8; scale bar: 1 mm.
745
746
NIITTYKOSKI ET AL.
TABLE 2
The influence of various drugs on the behavioural neurotoxicity of TMT
Drug, administration
route
Outcome measured
Effect
Reference
LE (m)
open field:
activity score
(crossing of grids)
3 hyperactivity in TMT:
0.5 in TMT, in controls
2.0 in TMT and in controls
4.0 in TMT, in controls
(104)
LE (m)
SD (m)
SD (m)
SD (m)
no effect in TMT,
5 in controls TMT
10 in controls, TMT
20 in controls, tendency in
TMT no effects on horizontal
activity and rearings
TMT impaired acquisition,
DGAVP improved learning
in non-learners
TMT impaired WM and PA,
increased LMA;
Tacrine improved WM
outcome in TMT, tendency
in PA and LMA outcomes
TMT impaired WM and PA,
increased LMA;
THIP improved WM in TMT,
no effects on PA and LMA
outcomes
PCP: improved WM, LMA
outcomes , no effects on PA
outcome;
ketamine and SKF 10,047:
no effects on any behavioural
outcome
(58)
LE (m)
d-amphetamine
0.5 mg/kg, i.p.
2.0 mg/kg
4.0 mg/kg
tested 5 weeks after TMT
Clonidine
5 mg/kg, i.p.
10 mg/kg,
20 mg/kg
tested 1926 days after
TMT
DGAVP 1
7.5 mg/kg, s.c.
tested 38 days after TMT
Tacrine
3 mg/kg, i.p.
started 1 week prior to TMT,
post-behavioural testing
administration
THIP 2
3 mg/kg, i.p.
started 1 week prior to TMT
SD (m)
(74)
PCP 3
5 mg/kg, i.p.
Ketamine
5 mg/kg
( ) SKF 10,047
5 mg/kg
started 1 week prior to TMT
JO 1784
1 mg/kg, s.c.
3 mg/kg
started 1 week prior to TMT
lever pressing in
non-learners (a forward
autoshaping task)
PA, WM, LMA
(started 3 weeks after TMT)
LMA, WM, PA
(started 3 weeks after TMT)
LMA, PA, WM
(started 3 weeks after TMT,
WM and passive avoidance
after withdrawal of drug)
(100)
(73)
(72)
(32)
1
DGAVP desglycinamide-8-arginine vasopressin; 2 THIP gaboxadol; 3 PCP phencyclidine; increased; no effect; decreased; LE
LongEvans; LMA locomotor activity in open field; m male; PA passive avoidance retention; RAM radial arm maze; SD SpragueDawley;
WM water maze acquisition.
747
748
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