Antagonisa Alfa 2 X Memoria

Neuroscience and Biobehavioral Reviews, Vol. 22, No. 6, pp.
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
Systemic 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
M. NIITTYKOSKI a, R. LAPPALAINEN a, J. JOLKKONEN a, A. HAAPALINNA b,
a ,*
P. RIEKKINEN SR a , c AND J. SIRVIO
a
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
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NIITTYKOSKI ET AL.
TABLE 1
The neurochemical effects of TMT
Rat strain
TMT dose, administration route
Effects, time from exposure
Reference
LAC:P (m)
F344 (m)
WI
LAC:P (m)
WI (m)
WI (m)
LAC:P (m)
F344 (m)
SD (m)
LE (m f)
10 mg/kg TMT-Cl, i.g.

5.25 mg/kg TMT-Cl, s.c.
8 mg/kg TMT, p.o.
8 mg/kg TMT-Cl, i.p.
3 3 mg/kg /once a week TMT-Cl, i.p.
14 1 mg/kg/alternate days TMT-base, i.p.
(12)
(117)
(49)
(12)
(66)
(66)
(12)
(117)
(31)
(55)
LAC:P (m)
WI
LE (m f)

8 mg/kg TMT, p.o.
14 1 mg/kg/alternate days TMT-base, i.p.
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)
7 mg/kg TMT-base, p.o.

9 mg/kg TMT-OH, p.o.
3 3 mg/kg /once a week TMT-Cl, i.p.
7 mg/kg TMT-base, i.g.
14 1 mg/kg/alternate days TMT-OH, i.p.
14 1 mg/kg/alternate days TMT-OH, i.p.
7 mg /kg TMT-Cl, i.g.
GLU cd 1d; hip 2 d

GLU hip, 1 w; frctx st
GLU hip 4 w
GLU binding hip cd sep ent, 2 d
GLU uptake CA1 sub, 13 w
GLU uptake CA1 sub, 45 w after first injection
GABA hip, 2 d
GABA hip frctx 1 w; st
GABA hip 22 d, am
GABA hip 52 d after first injection; brst cer
hyp st frctx
GABA A binding hip cd, 2 d
ACh hip 4 w
ACh Ch hyp st cortex hip, 52 d after first
injection
AChE # DG, 46 w
AChE # DG, 120130 d
ChAT CA3 7 d; CA1
ChAT DG 360 d; CA1 760 d
ChAT CA1 sub, 5 w after first injection
ChAT DG CA1 100120 d; cd
M 2 binding CA1 1 d; CA3 3 d
M 1 M 2 binding CA1 CA3c, 1 w
M 1 binding CA1 CA3, 2 w
M 1 M 2 binding sites hip, 22 d
M 1 M 2 binding hip 25 d
5-HT frctx 1 w; hip st
5-HT hip frctx st cer, 1 w
5-HT am/py 1 w; st olf sep hip
5-HT hyp; 7 mg/kg hip; am midbr
5-HT hip st 12 w; cer; frctx
5-HIAA cd 12 d; hip
5-HIAA hip frctx st, 1 w
5-HIAA hip 12 w; frctx st cer
5-HIAA hip hyp am midbr
5-HIAA/5-HT st nac sep am/py hip olf, 1 w
5-HIAA/5-HT st sep 24 w; frctx
NA hip, 12 d
NA hip frctx 1 w; st cer
NA am; hip midbr hyp
NA brst cer, 52 d after first injection
NA hip 12 w; cer; frctx st
b-adrenergic binding cerebral cortex, 22 d
b-adrenergic binding am/py frctx, 4 w
DA DOPAC frctx st, 1 w
DA DOPAC nac 1 w; st sep am/py olf
DA nac, 2 w
DA nac 23 w; st frctx
DA hip hyp am midbr
DA st 52 d after first injection; brst
DOPAC/DA st nac sep am/py olf, 1 w
DOPAC/DA st nac frctx, 24 w
DA receptor binding st 7 d
(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.
(31,32,54,73,74,112). Furthermore, deficits in acquisition of

active avoidance at the beginning of training have been
reported (31). However, one study reported that there were
no differences between controls and TMT-intoxicated rats
(using a 7 mg/kg TMT base) in either passive avoidance or
active avoidance learning, although intertrial activity was
elevated and extinction response was increased by TMT

(41). Moreover, TMT has been shown to produce effects on
operant behaviour, since TMT-intoxicated rats had higher
lever pressing rates under a fixed-ratio schedule of food
presentation (102) and TMT impaired the performance of
differential reinforcement at low response rates in an
a 2-ANTAGONIST AND HIPPOCAMPAL FUNCTION
operant schedule (123). These anatomical and behavioural

findings have made TMT-intoxicated rats an attractive
model for degenerative diseases such as AD, the most
common cause of dementia (121).
It is not understood how TMT can cause a selective
destruction of neurons, but it has been suggested that an
excess activation of the N-methyl-D-aspartate (NMDA)
type of glutamate receptors is involved (5). In TMT
intoxication the uptake of glutamate is reduced (Table 1),
and in vitro studies have shown that its efflux has been
elevated (24,67). Both effects may lead to overactivation of
glutamate receptors. The selectivity of damage might be due
to a protein named stannin, which is expressed in TMTsensitive neurons, e.g. in the hippocampus and entorhinal
cortex (108), and this protein may also be involved in the
apoptosis induced by TMT (107).
TMT intoxication may induce other characteristics of AD
than simply nerve cell apoptosis. The expression of a form
of amyloid precursor protein (APP) called APP-751 mRNA
was increased in CA1, but APP-695 mRNA levels were
unchanged in the rat hippocampus 25 days after TMT intoxication (75). It has been suggested that there is a correlation
between the increase in the APP-751/APP-695 mRNA ratio
and the number of senile plaques in the hippocampus in
Alzheimers patients (see (75)). Furthermore, a similarly
increased ratio has been reported in nucleus basalis of
behaviourally impaired aged rats (see (75)). However,
following TMT intoxication, rats do not develop amyloid
plaques (or neurofibrillary tangles) (121).
Gamma-amino butyric acid (GABA)-containing interneurons play an important role in the regulation of the excitability of principal cells, such as pyramidal neurons, in the
forebrain. TMT intoxication can affect GABA-mediated
neurotransmission (Table 1). The level of GABA was
increased and GABA A receptor binding was decreased in
the hippocampus soon after a large dose of TMT, whereas
the levels of GABA were reduced after smaller doses and
longer follow-up times (Table 1).
Different functional types of GABAergic interneurons
have been classified according to their neuropeptides and
calcium-binding proteins (35). Recently, the effects of TMT
on different hippocampal calcium-binding protein-positive
neurons were studied with immunocytochemistry (37,38).
Three weeks after TMT intoxication the number of calbindincontaining neurons was decreased, especially in the CA1
field, but parvalbumin- and calretinin-containing interneurons were preserved (37,38). These findings indicate
that TMT intoxication affects one type of dendritic inhibitory cell, but not perisomatic inhibitory cells or interneuronselective inhibitory cells. Several neuropeptides are colocalized with GABA in interneurons (35). Recently, the
effects of TMT on neuropeptides were studied (48,109). The
expression of neuropeptide Y mRNA was increased in hilar
interneurons and dentate granule cells 5 days after TMT
intoxication, whereas the number of somatostatin mRNAcontaining neurons was decreased 16 days after the intoxication (109). In addition, the neuropeptide Y content was
elevated in the entorhinal cortex 7 days after TMT intoxication (48). Neuropeptides, such as somatostatin, can also be
compromised in AD (34).
There are many studies into the effects of TMT intoxication on modulatory neurotransmitters such as acetylcholine
and the monoamines (Table 1). TMT intoxication produces
737
axonal sprouting within the cholinergic septohippocampal

system (e.g. (15,17)). This sprouting is an intriguing finding,
since it parallels the consequences of the lesion of the
entorhinal cortex, and is also a characteristic finding in
AD (see (121)). However, the cholinergic neurons of the
basal forebrain are not appreciably damaged by TMT (121),
whereas there is a profound neocortical cholinergic deficit in
AD (34). However TMT does cause a loss of M 1 and M 2
muscarinic receptor subtypes in both the hippocampus and
neocortex (Table 1, (71)).
Several reports have described the effects of TMT on the
serotonergic system. The levels of serotonin were decreased
and those of its metabolite, 5-HIAA, were elevated, indicating that the utilization of serotonin is increased in several
brain areas including the striatum, septum and hippocampus
(Table 1). The levels of noradrenaline may be reduced
(Table 1). The effects of TMT on the metabolites of
noradrenaline were investigated in one study, but the
changes were not statistically significant (12). However,
the b-adrenergic receptor ligand binding was increased 4
weeks after intoxication (59). This could be an adaptive
process following a reduction in levels of noradrenaline.
Interestingly, Andersson et al. (3) found that serotonin and
noradrenaline levels had recovered in the hippocampus
when measured 12 weeks after TMT intoxication. The
levels of dopamine were reduced in nucleus accumbens,
but TMT intoxication had no effect on the utilization of
dopamine (i.e. the ratio of DOPAC to DA) (Table 1). The
levels of serotonin and noradrenaline were decreased in the
temporal and frontal cortex in AD, but the concentration of
dopamine remained unchanged (34). The effects of TMT
intoxication on the histaminergic system are not known,
though this transmitter is compromised in AD (1).
In the neocortex and hippocampus, synaptic transmission
and plasticity are state dependent (6,10,44); see (56,118).
One candidate neurotransmitter associated with this modulation is noradrenaline. Both inhibitory interneurons and
principal neurons can be targets for noradrenergic synaptic
terminals in the hippocampus (36,61). In vitro and in vivo
physiological experiments have shown that noradrenaline
can enhance the excitability of principal neurons in the
forebrain (43,52,65,77,115). Furthermore, noradrenaline
can enhance the induction of long-term potentiation produced by high frequency stimulation in the synapses of
mossy fibres on CA3 pyramidal neurons (45). Noradrenaline
also modulates the long-term potentiation of fimbria-CA3
synapses (50) as well as the activity of neocortical neurones
(11).
The release of noradrenaline is regulated by a 2-adrenergic
autoreceptors which are located both in the soma and in the
presynaptic terminals of the noradrenergic neurons (see
(23)). The activation of those receptors inhibits the release
of noradrenaline, and therefore antagonists of a 2-adrenoceptors promote the release of noradrenaline in the brain
(92,106). Recently, studies have been undertaken to investigate the influence of a 2-adrenergic agents on cognition in
animals and humans (23). The systemic administration of
idazoxan or atipamezole, selective antagonists of a 2adrenoceptors, has been found to enhance the excitability
of granular neurons to the stimulation of the perforant path
(90,126). The same doses were found to improve intermediate-term retention in the radial arm maze task (126) and
memory retrieval in the linear arm maze task (91). In
738
NIITTYKOSKI ET AL.
addition, atipamezole improved the choice accuracy of rats

in an attentional task when the intensity of the visual stimuli
was reduced (96). It could be speculated that the administration of a drug would direct the attention of rats towards
pertinent cues during the sampling phase of the radial arm
maze task, improving their intermediate-term retention or
retrieval of learned material.
Since our goal is to develop symptomatic treatment for
dementia, it should be noted that none of the abovementioned studies investigated the influence of a 2-antagonists on the performance of cognitively impaired rats such
as those with lesions in the hippocampal formation and
related brain areas, which leads to the isolation of the hippocampus from the neocortex. Therefore, the present study
investigated whether a selective antagonist of a 2-adrenoceptors, atipamezole, could facilitate short-term or longterm memory in TMT-intoxicated rats, which exhibit
neuronal damage in the limbic system. These memory functions were assessed with the radial arm maze task, using the
version in which working memory-type errors (revisits to
arms) and reference memory-type errors (visits to nonbaited arms) can be investigated. In addition to potential
facilitation of neuronal transmission and plasticity by the
increased activity of noradrenergic neurons (65,82,84,89),
the enhancement in the release of acetylcholine in the
neocortex by atipamezole (105) could be beneficial in
TMT rats, because these animals have reduced levels of
muscarinic receptor binding in the cortex (71). The possible
influences of atipamezole on hyperactivity and the disruption of grooming behaviour in TMT-intoxicated rats were
also considered to be valuable preclinical information, since
the treatment of non-cognitive symptoms of AD, such as
wandering and disruption of personal grooming, can be of
great importance in the everyday life of patients. Therefore,
the performance of TMT-intoxicated rats was tested in the
open-field task. Moreover, the influence of atipamezole on
hyperactivity produced by TMT was considered to be of
special interest, since the symptoms of TMT intoxication
resemble the behavioural syndrome induced by MK-801, a
non-competitive antagonist of N-methyl-D-aspartate receptors (9,42,80,124), a drug used as a model for psychosis
(76), and it has recently been suggested that some atypical
neuroleptics can act as antagonists at a 2-adrenoceptors (70).
Interestingly, atipamezole was found to reduce scopolamineinduced hyperactivity in rats (69). Before the drug trials
were started, the performance of the TMT group was also
tested in the water maze task which was used to assess
sensori-motor control (by examining the ability of rats to
swim to a visible platform).
MATERIALS AND METHODS
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
(R36, Lactamin, Stockholm, Sweden); subsequently they

were maintained at approximately 8085% of their freefeeding body weight by limiting their food access to 14
16 g per day throughout the duration of radial arm maze
tests. Behavioral testing was initiated after 1 week of
restricted access to food. Water was available ad libitum.
Pharmaceutical agents
Trimethyltin chloride (TMT, Research Biochemicals
Inc., USA) was dissolved in saline and injected intraperitoneally (i.p.), 8 mg/kg (i.e. 6.6 mg/kg as a free base).
Previously, doses between 6 and 7 mg/kg (as the free
base) have been used to produce the behavioural syndrome
of TMT intoxication in rats as well as to study the distribution of neuronal degeneration induced by TMT (e.g.
(7,31,41,123)).
Atipamezole (4-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1Himidazole) is a highly selective and specific a 2-adrenoceptor antagonist (92,111). In receptor binding studies,
atipamezole is reported to have about 100 times higher
affinity for a 2-adrenoceptors and an a 2/a 1 selectivity ratio
over 100 times higher than that of idazoxan and yohimbine.
In studies with isolated organs, atipamezole is a more potent
a 2-adrenoceptor antagonist and has about 200 times higher
relative a 2/a 1 blocking ratio than idazoxan (111). Atipamezole has an almost equal affinity for the different a 2adrenoceptor subtypes (88). Atipamezole penetrates rapidly
into the brain (8), causing a dose-dependent increase in the
release of central noradrenaline and serotonin (92). In the
present study, atipamezole hydrochloride (Orion Pharma,
Turku, Finland) was dissolved in saline and injected subcutaneously, 300 mg/kg (1.0 ml/kg).
Behavioural experiments
Radial arm maze task
The 10-arm maze apparatus has been described previously (80,83). The rats were habituated to handling and
then to the maze. In the first day of maze habituation, food
pellets (45 mg Precision pellets, Bio-Serv, NJ, USA) were
in the centre of the arena and all arms were closed. In the
second session, the rat had access to one arm, which was
baited. The rats were allowed to explore the maze for
10 min on each testing session. Gradually, more arms
were opened, and food pellets were located only at the
end of every baited arm. Finally, the rats were able to search
for food pellets in the maze with all the arms open.
In order to assess both short-term and long-term memory,
a rat was trained to obtain food pellets from only five locations in the 10-arm maze. The pattern of baited arms was the
same from day to day but could vary between animals (five
different configurations) in order to reduce the aid of olfactory cues left by a previous rat. The rat was put into the maze
with every door open. When the rat had succeeded in obtaining all the food pellets, it was returned to its home cage.
Maximum testing time was 10 min. The maze was cleaned
between animals. A correct choice was recognized when the
rat visited a food well of the baited arm. Long-term memory
errors were assessed by the number of entries to non-baited
arms, and short-term memory errors were assessed by the
number of entries to previously visited arms during a trial.
The number of arm entries per minute was taken as a
739
FIG. 1. Schedule of the study. The numbers represent the days from TMT administration.
measure of locomotor activity. The number of correct

choices before the first error (a visit to an empty arm) was
also calculated. The training was continued until rats
showed a consistent choice accuracy above the chance
levels (e.g. approximately 1.6 correct choices before the
first error, for which the chance level is 0.8).
TMT administration
After this initial training phase in the radial arm maze
task, the rats were given a free-feeding period of 12 days
and were then treated with TMT chloride (8 mg/kg, n 22)
or saline (1 ml/kg, n 16). The rats were allowed to recover
for 28 days. The rats were given food pellets, which were
made as palatable as possible, inside their cages. If a rat
refused to eat these pellets, it was provided with some
chocolate, apple or banana according to its preference.
The rats were given also saline intraperitoneally. In spite
of this post-intoxication treatment, seven TMT-treated rats
died 522 days after the administration of the toxin. The
weight of the surviving rats was 91%, 83% and 91% of
saline-treated rats on days 3, 10 and 24, respectively, after
TMT administration. The TMT-intoxicated rats exhibited
the signs of TMT syndrome, such as hyperreactivity, resistance to handling and tail mutilation (30).
The open-arena test
To assess their exploratory behaviour, the rats were tested
in an open arena. The apparatus has been described previously (69). Before the start of testing in the open arena,
the rats were habituated to the open arena testing board and
environment for 3 min each day for three days.
The open arena test was performed 31 days after TMT

intoxication. The animals were placed in the open arena for
a 9 min period (3 3 min sessions interrupted by a 10 s
period to load the computer). The floor and walls of the open
arena were cleaned between animals. Locomotor activity,
expressed by the path length, was recorded for each animal.
The number of times the rat reared up on its hind legs, the
number of groomings and the number of fecal boli were
counted by the experimenter.
The water maze task
This task was aimed to assess spatial memory (navigation
cued by distal cues) and non-mnemonic factors using the
non-spatial version (navigation cued by the visibility of the
platform, the position of which was also altered trial by trial
in order to minimize the contribution of spatial memory).
However, the hidden platform version was not assessed,
because TMT-intoxicated rats were severely impaired
even when the platform was visible. The water maze
apparatus has been described previously (69,86). The
swim paths were monitored by a video camera linked to a
computer through an image analyzer (HVS Image, UK).
The computer software (made by HVS Image) calculated
total distance and time swum as well as the percentage of
time spent in each quadrant and annuli.
The water maze testing was initiated 5 weeks after TMT
intoxication. In the habituation trial, the rats were allowed to
swim for 90 s in the pool, which did not contain the platform. Two days later, the rats were trained to find a visible
platform (top 1.5 cm above the water line), which was
located in the south-west quadrant during the first part of
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.
training. Training was continued for 2 days (4 trials/day,

maximum duration 60 s, 10 s reinforcement on the platform).
In the second part of the training, the visible platform was
moved to a different quadrant after each trial. Training was
continued for 4 days (2 trials/day, maximum duration 60 s,
10 s reinforcement on the platform). If the rat failed to find
the platform within 60 s, it was put onto it for 10 s.
Reacquisition of the radial arm maze task and open-arena
testings after vehicle or atipamezole injections
After water maze testing, the rats were returned to
restricted feeding to reduce the weight to approximately
85% of weight controls. Then (68 days after the previous
testing in the radial arm maze) the rats were retrained for the
radial arm maze task for 5 days. During the last three days,
all the rats were injected with saline (1 ml/kg, s.c.) to
habituate them to the injections.
The TMT-intoxicated rats and their controls were divided
randomly to groups to be treated with either atipamezole
hydrochloride (300 mg/kg, s.c., TMT: n 8 and controls:
n 8) or saline (TMT: n 7 and controls: n 8) before
daily testing either in the radial arm maze task or in the
open-arena task (see schedule in Fig. 1). One TMTintoxicated rat treated with atipamezole died on the first
day of testing (about 1 h after atipamezole injection).1
Food intake
In addition, food intake was measured. The animals were
given more food than they normally consumed and the
amount of food was calculated 24 h later. The baseline
measurements were done 8 and 4 days before TMT intoxication, when the rats were free-feeding. To assess the effect
of TMT intoxication, the food intake was measured 8 days
after the TMT intoxication. The final measurement investigated the effect of atipamezole on food intake (98 days after
TMT administration, following the last test in the radial arm
maze).
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
Behavioural testings before atipamezole treatment

Open-arena test
The TMT group travelled a longer path length than their
controls (a significant group effect, F(1, 29) 5.57, p
0.05), and this difference between the groups in the path
length increased with time within the testing session (a
significant interaction between the group and testing effect,
F(2, 58) 4.85, p 0.05) as shown in Fig. 2. The number
of rearings did not differ between controls and TMT group
(F(1, 29) 0.23, p 0.1), but there was a significant
interaction between group and testing effects (F(2, 58)
4.77, p 0.05). The number of groomings was decreased in
TMT-intoxicated rats (F(1, 29) 22.92, p 0.001),
whereas the number of fecal boli produced by TMT-intoxicated rats (6.1 1.1, mean SEM) was significantly
increased in comparison with controls (0.3 0.3)
(F(1, 29) 27.29, p 0.001).
The water maze task with a visible platform
In the habituation trial, TMT-intoxicated rats swam less
than their controls (a significant group effect (F(1, 29)

22.92, p 0.001) in total distance (in metres, mean
SEM); controls: 21.3 0.7 (n 16) and TMT: 14.0 0.1
(n 15)).
In the swim-to-platform test (platform kept in a constant
position), TMT-intoxicated rats had significantly longer
escape latencies (F(1, 29) 400.3, p 0.001) and distances
(F 109.7, p 0.001) than their controls, and their
swimming speed was slower than that of the controls (F
16.3, p 0.001), as shown in Fig. 3A.
In another swim-to-platform test (platform moved to a
different location in each trial), TMT-intoxicated rats had
significantly increased escape latencies (F(1, 29) 418.2,
p 0.001) and distances (F 189.1, p 0.001). Swimming speed did not differ between controls and TMTintoxicated rats (a non-significant group effect (F 0.2,
p 0.1) (Fig. 3B)).
Retention of radial arm maze task
During the retesting phase of the radial arm maze task,
TMT-intoxicated rats (n 15) made more re-entries to the
visited arms (11.17 1.54) than controls (n 16) (5.63
0.95, mean SEM; a significant group effect, F(1, 29)
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).
9.64, p 0.01). Importantly, both groups performed close

to a chance level in memory scores (e.g. 4.5 for the number
of the visits to the non-baited arms and 0.8 for the number of
correct choices before the first error) even though these
scores were significantly better after the acquisition phase of
this task before vehicle or TMT administration. This indicates that even the controls had forgotten the task before the
tests were performed with atipamezole.
The effects of atipamezole treatment on the performance of
rats
Reacquisition of radial arm maze task
TMT-intoxicated rats made less correct choices before
the first error (F(1, 26) 16.45, p 0.001), visited more
incorrect arms (F 8.08, p 0.01) and made markedly
more re-entries to visited arms than controls (F 148.66,
p 0.001) during the reacquisition phase, as shown in
Fig. 4. Atipamezole treatment did not influence these parameters in either control or TMT groups (p 0.1 for all
parameters and their interaction with the group effect, i.e.
TMT vs controls) (Fig. 4).
TMT-intoxicated rats made more arm entries in a given
time than control rats (a significant group effect, F(1, 26)
22.72, p 0.001) (Fig. 4). Atipamezole increased this kind
of activity (a significant treatment effect, F(1, 26) 8.30,
p 0.01), but its influence on behavioural activity did not
differ between controls and TMT-intoxicated rats (a nonsignificant interaction between treatment and group effects,
F(1, 26) 0.02, p 0.1). The influence of atipamezole on
behavioural activity became clearer as the testing progressed (a significant interaction between treatment effect
and trial block, F(7, 182) 3.13, p 0.01) (Fig. 4).
Open-arena task
TMT-intoxicated rats had significantly longer path
lengths than controls in every testing session (e.g. a significant group effect, F(1, 26) 68.82, p 0.001 in the third
testing session), and this difference became clearer with
time within each test session (a significant interaction
between group effect and time effects, F(2, 52) 11.2,

p 0.001), as shown in Fig. 5. Atipamezole slightly
increased path length on the third testing, F(1, 26) 3.24,
p 0.08 (whereas on the first and second testings the
treatment effect was not significant, p 0.1), but this
effect did not differ between the TMT group and their
controls (a non-significant interaction between treatment
effect and group effect, F(1, 26) 1.34, p 0.1) (Fig. 5).
TMT-intoxicated rats made more rearings in all testings
(e.g. a significant group effect in the third testing, F(1, 26)
7.54, p 0.05). This difference between groups became
more prominent over time within each testing session (e.g. a
significant interaction between group effect and time effect
in the third testing, F(2, 52) 3.58, p 0.05), since
controls, but not TMT-intoxicated rats, made less rearings
with time within a testing session. Atipamezole did not
significantly influence the number of rearings in the TMT
group or their controls (e.g. a non-significant treatment
effect, F 0.00, p 0.1, and interaction between treatment
and group effects, F 0.44, p 0.1 in the third testing)
(Fig. 5).
The incidence of groomings was slightly lower in TMTintoxicated rats in comparison with their controls (a significant group effect, F(1, 26) 7.22, p 0.05 in the third
testing). The influence of atipamezole and these interactions
with the group effect was not significant in any of the
tests (p 0.1).
The number of fecal boli was consistently higher in TMTintoxicated rats than in their controls, and atipamezole
increased the number of fecal boli consistently in controls
(Fig. 5). However, no significant differences were found in
any of the tests (p 0.05).
Food intake
Food intake during a 24 h period was equal in controls
and TMT-intoxicated rats before TMT intoxication, as well
as between controls and those TMT-intoxicated rats which
survived when assessed 8 days after the administration of
TMT (Fig. 6). When measured after the completion of the
radial arm maze testing, including atipamezole treatments,
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.
TMT-intoxicated rats consumed significantly more food

than controls (F(1, 29) 6.82, p 0.02), and this group
difference was not affected by treatment (saline vs atipamezole) (F(1, 29) 0.18, p 0.1). In general, the amount
of food consumed was higher than in the previous measurements, since the rats were on restricted feeding immediately
before this last testing point.
also apparent in the cortical areas. Interestingly, the anterior

neocortex seemed to be less severely affected than the
posterior neocortex, as judged by the shrinkage of the
cortex (Fig. 7B and D). Posterior spreading of cortical
damage by TMT was also demonstrated by the almost
complete disappearence of the entorhinal cortex.
DISCUSSION
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.
was reported in rats weighing about 440 g treated with

7 mg/kg TMT (as a free base (30)). Recently, Alessandri
et al. (2) reported 40% mortality using the same dose but a
different rat strain. The present death rate may be due to the
high body weight (and age) of the animals being trained for
the radial arm maze task before TMT administration. However, body weight prior to exposure did not differ between
rats surviving (mean 417 g) and succumbing (mean 416 g).
In addition, there are known to be differences between rat
strains in their sensitivity to the neurotoxic effects of TMT
(21,64).
Histological examination of Nissl-stained sections at 16
weeks after intoxication indicated a severe atrophy in the
hippocampus and the cerebral cortex. Moreover, the posterior

neocortex seemed to be more severely affected, which agrees
with a previous study (7), although that study had shorter
follow-up times than the present study. One study, using a
relatively long follow-up time (13), employed a different kind
of TMT administration schedule, but the effects of TMT on
hippocampal and cortical shrinkage, as well as on enlargement
of ventricles, were similar to those found in the present study.
Influence of TMT intoxication on the performance of rats
The results from the open-arena and radial arm maze
tasks indicate that TMT intoxication caused persistent
hyperactivity in the rats, which is in good agreement with

previous studies (see (57)). For example, Swartzwelder et al.
(102) found a more than 3-fold increase over controls in the
open-field activity of rats administered 7 mg/kg TMT-Cl
when they were tested 40 days after exposure. More
recently, Earley et al. (31) found that 8 mg/kg, but not 6
or 7 mg/kg, TMT-Cl increased ambulation approximately 2fold when it was measured 21 days after exposure. After
intoxication with 8 mg/kg TMT-Cl, the increase in ambulation was approximately 2-fold at one month and 3-fold at
two months after exposure. Hyperactivity may be a consequence of the damage to the hippocampus (60,68), possibly
due to deficits in adaptive responses to novelty against
familiarity, and behavioural inhibition (51). Interestingly,
the locomotor activity of TMT-intoxicated rats was less than
that of controls in the habituation test of water maze. (Thus,
in one environment TMT intoxication is associated with
hyperactivity, whereas in another it reduces locomotor
activity.) The previous studies (31,41,93,123) did not
report data on the influence of TMT intoxication on swimming speed (even though escape latency was used to express
the acquisition of the water maze task). The reduced
locomotor activity in a swimming pool could indicate an
enhanced emotional response to novel environments. It
should be noted that TMT-intoxicated rats produced more
fecal boli in open-arena testing and this is considered as an
index of emotional response. It is evident that TMT
intoxication affects also the amygdala, which is known to
be important in mediating emotions. In addition, the selfgrooming of TMT-intoxicated rats was disrupted in the
open-arena task. These findings are in good agreement
with previous studies (18,30).
The feeding data suggest that food restriction may
increase the food intake of TMT-intoxicated rats more
than in the controls. Thus, the effect of TMT-intoxication
on food intake may be dependent on food restriction,
because no effect of TMT was observed after eight days
of ad libitum feeding. However, another possibility is that
the influence of TMT on food intake depends on the postintoxication time point. When the rats are receiving a
restricted diet, the value of food could be higher in TMTintoxicated rats. This could partly explain their increased
behavioural activity in the radial arm maze task. In addition,
it is known that the state of satiety can influence a rats
performance in the open-field task (51).
Hyperactivity can result as a secondary consequence of
the loss of spatial memory (114). Indeed, TMT-intoxicated
rats exhibited an increased number of errors, indicative of a
deficit both in short-term and in long-term memory during
the reacquisition phase of the radial arm maze task. The
findings on the reacquisition phase, especially the perseverating performance of TMT-intoxicated rats, agree with a
previous study ((113), using TMT 6.0 mg/kg as a base),
even though it should be recognized that the present study
investigated relative contributions of both reference and
working memory errors. Moreover, TMT-intoxicated rats
made more working memory errors in an unbaited 6-arm
radial tunnel maze (2). Swartzwelder et al. (103) found a
profound deficit akin to perseverative behaviour in rats after
7.0 mg/kg TMT-Cl when they were tested in a series of
HebbWilliams maze problems. The deficit could be the
result of hippocampal lesion (78).
The disruption of olfactory memory (e.g. due to a
745
neuronal loss in the olfactory tubercle and pyriform cortex,

(7,19)) could, at least partly, explain the increased perseveration in the radial arm maze task and reduced habituation
in the open-arena task, since it is possible that a rat uses its
own olfactory cues, in addition to allocentric visual and
egocentric tactile cues, to track visited places. In addition,
the deficit in visual discrimination could be a factor contributing to their poor performance in the radial arm maze
task. Even though previous histological studies have indicated that the visual system is fairly well preserved in TMTintoxicated rats (7,19), abnormalities in visual evoked
potentials have been found (29).
In fact, TMT-intoxicated rats were not impaired in the
acquisition of lightdark discrimination task (49,122).
Ishikawa et al. (49) reported that administration of 6 mg/
kg TMT did not affect the percent correct response during
the acquisition or retention phase. In contrast, the rats given
6 mg/kg TMT (as a free base) made more correct responses
in the reversed version of the same task (122). These
findings were unexpected, since it is known that acquisition
of visual discrimination tasks may also be impaired after
surgical hippocampal lesions (see (122)).
Interestingly, we found that TMT-intoxicated rats were
severely impaired in the water maze task in the version that
should not be dependent on spatial (relational) memory.
Four previous studies (using TMT in a range of 67 mg/
kg as a free base) showed a clear impairment in the
acquisition of hidden platform version (expressed as
escape latency), but none of them reported a control
experiment using a visible platform task (31,41,93,123).
However, Hagan et al. (41) found that TMT-intoxicated
(7 mg/kg as a free base per os) and controls did not differ in
the visual discrimination version of the water maze task,
even though it was more difficult for rats, whereas there was
a clear difference between the groups in the spatial version
of the water maze task. The lowest dose (5 mg/kg as a free
base) did not impair water maze learning (41). The discrepancies between the present results and those of Hagan
et al. on cued navigation could be related to the more severe
brain damage in the present study.
It should be noted that blind rats are not profoundly
impaired in the reference memory version of the Morris
water maze (53). Blind rats performed better than atropinetreated rats, although they were worse than controls. In
addition, there was no clear difference between blind rats
and atropine-treated rats in a cued version of the water
maze. Furthermore, there were no differences between
controls, atropine-treated and blind rats in the straight
swim version of the water maze (53).
One should consider possibilities other than primary dysfunction in visual discrimination (deficit in retinogeniculate-striate cortex transmission) in the interpretation
of the present data on the water maze task. The behavioural
deficits of TMT-intoxicated rats found in the present study
resemble the behavioural abnormalities (hyperactivity,
deficits in grooming behaviour and in a swim-to-platform
task) observed in rats with p-chlorophenylalanine treatment
(to deplete serotonin levels in the brain) combined with the
administration of a high dose of scopolamine, a muscarinic
antagonist (110). As discussed by Vanderwolf, this syndrome was akin to deficits seen in decorticated animals, and
it was more severe than the combined ablation of the
hippocampus and amygdala when this was assessed using
746
NIITTYKOSKI ET AL.
TABLE 2
The influence of various drugs on the behavioural neurotoxicity of TMT
Rat strain TMT dose, administration

route
Drug, administration
route
Outcome measured
Effect
Reference
LE (m)
7 mg/kg TMT-Cl, p.o.
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)
6 mg/kg, TMT-base, p.o.
hole board task:

hole visits,
crossing scores,
rearings
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)
TMT impaired PA and RAM,

increased LMA;
1: improved RAM in TMT,
in controls and on
other outcomes
3: LMA and improved
RAM and PA in TMT,
in controls
(74)
PCP 3
5 mg/kg, i.p.
Ketamine
5 mg/kg
( ) SKF 10,047
5 mg/kg
JO 1784
1 mg/kg, s.c.
3 mg/kg
lever pressing in
non-learners (a forward
autoshaping task)
PA, WM, LMA
(started 3 weeks after TMT)
LMA, WM, PA
LMA, PA, WM
(started 3 weeks after TMT,
WM and passive avoidance
after withdrawal of drug)
LMA, PA, RAM

(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.
the open-field, swim-to-platform and Lashley III maze tests

(28). It was postulated to result from a dysfunction in the
control of motor output by sensory cues, i.e behavioural
organization, rather than loss of learning and memory, or
primary sensory dysfunction (110). Interestingly, it has been
reported that TMT-intoxicated rats have a modest reduction
in the levels of serotonin and muscarinic binding in the cerebral
cortex (3,71,117), which could augment the functional
consequences of neuronal loss in the cerebral cortex (7).
Taken as a whole, the present data suggest that
behavioural dysfunctions (reduced habituation, reduced
self-grooming, impairment in a swim-to-platform task,
hyperactivity, impaired working and reference memory)
induced by exposure to an intermediate to high dose of TMT
appear to represent a model for global dementia rather than
a specific deficit in relational (declarative) memory. However, the present data do not contradict the possibility that
exposure to a lower dose of TMT ( 6 mg/kg) could induce
more specific associational deficits devoid of hyper-reactivity,
especially when these are assessed with delay-dependent
operant tasks (14,22).
Influence of atipamezole on the performance of control and

TMT-intoxicated rats
The present results do not provide evidence that an a 2antagonist, atipamezole, can improve mnemonic performance either in TMT-intoxicated or control rats. This lack
of efficacy in the controls cannot simply be attributed to
inadequate dosing, because previous studies have indicated
that the systemic administration of 300 mg/kg (used in the
present study), but not 30 or 1000 mg/kg, atipamezole
enhanced the excitability of granular cells to the stimulation
of the perforant path as reflected in the increased size of the
population spike, this being unaccompanied by any significant increase in the EPSP slope (126). In addition, this most
effective dose of atipamezole, known to be sufficient to
increase the release of noradrenaline in the brain (92),
improved the intermediate-term (6 h) retention of the
radial arm maze task (delayed non-matching to position
version) (126). Furthermore, 300 mg/kg atipamezole
improved the acquisition of a linear arm maze task (40),
and atipamezole (301000 mg/kg) improved the choice
accuracy of rats in the attentional task when the intensity of

the visual stimuli was reduced (96). However, it should be
noted that the working memory, as assessed by the delayed
non-matching to position task in an operant chamber, and
reference memory, as assessed by the water maze task, were
not improved by atipamezole (103000 mg/kg) in either
adult or aged rats ((95,98) and unpublished data).
In fact, atipamezole increased the behavioural activity of
control and TMT-intoxicated rats. This agrees with previous
findings showing that acute administration of 3001000 mg/
kg increased premature responses (impulsivity) in an attentional task and the time to obtain a cumulative period of
20 min immobility in electrophysiological recordings
(85,96,97). In addition, other specific a 2-antagonists have
been found to increase locomotor and exploratory activity in
the open-arena task (27). The present data indicate that
TMT intoxication does not influence the mechanisms by
which atipamezole activates these behavioural functions.
The likely candidates, i.e. activation of the locus coeruleus
noradrenergic neurons and subsequent indirect activation of
dopaminergic neurons in the ventral tegmental area projecting to limbic neocortex and striatum (39), have not been
demonstrated to be affected by TMT intoxication (at the
dose used in the present study) (7). Recent data indicate that
300 mg/kg atipamezole could reduce scopolamine (0.5 mg/
kg)-induced ambulation in the open-arena task even though
it slightly increased it when administered alone (69).
Taken together, the present data suggest that atipamezole,
a selective and specific antagonist of a 2-adrenoceptors, did
not alleviate the behavioural disturbances in TMTintoxicated rats, but did enhance the behavioural activity
in rats, at least when they were in a familiar environment.
Previous studies on the alleviation or prevention of
behavioral neurotoxicity of TMT
Only a few studies have investigated the influence of
drugs on the behavioural symptoms of TMT-intoxicated
rats (Table 2). Swartzwelder et al. (104) found that TMT
intoxication influenced the doseresponse relationship of
d-amphetamine on the locomotor activity of rats in the
open-field task. Those findings are in line with the results
of recent studies showing that hippocampal lesions sensitize
rats to the hyperactivity induced by d-amphetamine
(62,116). Since the doseresponse relationship of d-amphetamine is an inverted U-shape, Swartzwelder et al. found that
the highest d-amphetamine dose reduced the locomotor
activity of TMT rats whereas this dose increased the
locomotor activity of controls. The authors made an interesting proposal that TMT rats could be considered as a
model for attention deficit hyperactivity disorder (ADHD).
However, Messing et al. (58) found that TMT rats tended to
be less sensitive to the sedative effects of clonidine, a partial
agonist of a 2-adrenoceptors, which has been found to
alleviate the symptoms of ADHD patients (46). The apparent discrepancy between the results of Swarztwelder et al.
(104) and Messing et al. (58) could be due to a dosedependent influence of TMT on noradrenergic neurons.
The medium dose increases b-adrenergic receptor binding
(possibly due to loss of afferent input), whereas lower and
higher doses do not share this effect (59).
One study has investigated the influence of a drug on the
learning of TMT-intoxicated rats. Sparber et al. (100)
747
reported that the systemic administration of a vasopressin

analogue improved the acquisition of a lever pressing task in
the subgroup of TMT rats which were non-learners for the
task.
Another line of research has investigated how the neurotoxicity of TMT can be prevented by different kinds of
compounds (Table 2). The results of OConnell, Earley
and their colleagues indicate that the systemic administration of tacrine, PCP, THIP and JO 1784 can diminish the
behavioural outcomes of TMT intoxication. Interestingly,
the deficits in the water maze task and radial radial arm
maze were alleviated whereas both the locomotor hyperactivity and passive avoidance retention were prevented
only with a higher dose of JO 1784. Neuroanatomical substrates for this behavioural selectivity (spatial learning vs
locomotor activity) still have to be investigated. The
mechanisms of neuroprotection could include the antagonism of NMDA receptors by tacrine and PCP. In addition,
none of the studies has investigated whether post-intoxication treatment could improve the outcome, possibly by preventing the progressive degeneration induced by a single
dose of TMT.
ACKNOWLEDGEMENTS
The authors thank Kirsi Puurunen for help in perfusions

and Nanna Huuskonen for histological assistance. Ewen
MacDonald is acknowledged for revising the language of
the manuscript.
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Neuroscience and Biobehavioral Reviews, Vol. 22, No. 6, pp.

Systemic Administration of Atipamezole, a

TMT dose, administration route

Effects, time from exposure

10 mg/kg TMT-Cl, i.g.

10 mg/kg TMT-Cl, i.g.

7 mg/kg TMT-base, p.o.

GLU cd 1d; hip 2 d

(31,32,54,73,74,112). Furthermore, deficits in acquisition of

elevated and extinction response was increased by TMT

a 2-ANTAGONIST AND HIPPOCAMPAL FUNCTION

operant schedule (123). These anatomical and behavioural

axonal sprouting within the cholinergic septohippocampal

addition, atipamezole improved the choice accuracy of rats

(R36, Lactamin, Stockholm, Sweden); subsequently they

a 2-ANTAGONIST AND HIPPOCAMPAL FUNCTION

measure of locomotor activity. The number of correct

The open arena test was performed 31 days after TMT

training. Training was continued for 2 days (4 trials/day,

a 2-ANTAGONIST AND HIPPOCAMPAL FUNCTION

Behavioural testings before atipamezole treatment

than their controls (a significant group effect (F(1, 29)

9.64, p 0.01). Importantly, both groups performed close

between group effect and time effects, F(2, 52) 11.2,

a 2-ANTAGONIST AND HIPPOCAMPAL FUNCTION

TMT-intoxicated rats consumed significantly more food

also apparent in the cortical areas. Interestingly, the anterior

was reported in rats weighing about 440 g treated with

hippocampus and the cerebral cortex. Moreover, the posterior

a 2-ANTAGONIST AND HIPPOCAMPAL FUNCTION

hyperactivity in the rats, which is in good agreement with

neuronal loss in the olfactory tubercle and pyriform cortex,

Rat strain TMT dose, administration

7 mg/kg TMT-Cl, p.o.

6 mg/kg, TMT-base, p.o.

hole board task:

6 mg/kg TMT-base, p.o.

8 mg/kg TMT-Cl, i.p.

8 mg/kg TMT-Cl, i.p.

8 mg/kg TMT-Cl, i.p.

8 mg/kg TMT-Cl, i.p.

TMT impaired PA and RAM,

LMA, PA, RAM

the open-field, swim-to-platform and Lashley III maze tests

Influence of atipamezole on the performance of control and

a 2-ANTAGONIST AND HIPPOCAMPAL FUNCTION

accuracy of rats in the attentional task when the intensity of

reported that the systemic administration of a vasopressin

The authors thank Kirsi Puurunen for help in perfusions

a 2-ANTAGONIST AND HIPPOCAMPAL FUNCTION

postnatal trimethyltin or triethyltin treatment on CNS catecholamine,

Riekkinen, P. J. Sr, The effects of D-cycloserine and MK-801 on the

presynaptic a 2-receptor-mediated inhibition of norepinephrine

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