Functional dissociation between serotonergic pathways in dorsal and ventral hippocampus in psychotomimetic drug-induced locomotor hyperactivity and prepulse inhibition in rats

Altered hippocampal function and brain serotonin activity are implicated in the development and symptoms of schizophrenia. We have previously shown that lesions of the median raphe nucleus, but not the dorsal raphe nucleus, produced a marked enhancement of locomotor hyperactivity induced by phencyclidine and disruption of prepulse inhibition. The dorsal and ventral hippocampus receive serotonin projections predominantly from the median raphe nucleus and dorsal raphe nucleus, respectively. Therefore, we investigated the effect of local lesions of serotonin projections into the dorsal and ventral hippocampus on psychotomimetic drug-induced locomotor hyperactivity and prepulse inhibition. Male Sprague-Dawley rats were anaesthetized with pentobarbitone and stereotaxically microinjected with 5 microg of the serotonergic neurotoxin 5,7-dihydroxytryptamine into either the dorsal or the ventral hippocampus. Two weeks after surgery, dorsal hippocampus-lesioned rats showed a 100% enhancement of the locomotor hyperactivity caused by phencyclidine treatment and a slight but significant reduction of the effect of amphetamine. Prepulse inhibition was significantly disrupted in lesioned rats and serotonin levels in the dorsal hippocampus were reduced by 80%. Rats with lesions of the ventral hippocampus showed 85% depletion of serotonin and partial disruption of prepulse inhibition, but no significant changes in the effect of phencyclidine or amphetamine. These results suggest that serotonin projections from the median raphe nucleus to the dorsal hippocampus play an important role in locomotor hyperactivity and prepulse inhibition in rats, animal models of aspects of schizophrenia. This suggests that these serotonin projections may be involved in the pathophysiology of schizophrenia symptomology.     

Brain serotonin depletion by lesions of the median raphe nucleus enhances the psychotomimetic action of phencyclidine, but not dizocilpine (MK-801), in rats

We have previously shown that brain serotonin depletion by lesions of the median raphe nucleus (MRN) causes enhancement of phencyclidine-induced locomotor hyperactivity [S. Kusljic, D.L. Copolov, M. van den Buuse, Differential role of serotonergic projections arising from the dorsal and median raphe nuclei in locomotor hyperactivity and prepulse inhibition, Neuropsychopharmacology 28 (2003) 2138-2147]. In this study, we extend our previous work by (1) comparing the effect of phencyclidine with that of another NMDA receptor antagonist, dizocilpine (MK-801); (2) investigate behavioral changes in more detail; (3) assess in detail the effect of raphe lesions on regional serotonin levels in the brain. Male Sprague-Dawley rats received microinjection of the serotonergic neurotoxin 5,7-dihydroxytryptamine into the MRN or dorsal raphe nucleus (DRN). The effects of treatment with saline, phencyclidine and MK-801 on locomotor activity were determined 2 weeks after the surgery. MRN lesions caused serotonin depletion in the dorsal hippocampus, whereas DRN lesions caused serotonin depletion in the frontal cortex, striatum and ventral hippocampus. There was a significant increase in phencyclidine-induced locomotor hyperactivity in the MRN-lesioned group compared to sham-operated controls. Further analysis of behavior showed that phencyclidine-induced hyperambulation, but not stereotypy or rearing, was significantly higher in MRN-lesioned rats compared to controls. In contrast, there was no significant effect of the lesions on the psychotomimetic effect of MK-801. These results indicate that a hyposerotonergic state induced by destruction of projections from the MRN leads to altered brain circuitry that is responsible for the regulation of phencyclidine-but not MK-801-induced locomotor hyperactivity. Thus, MRN projections may play an inhibitory role in mechanisms involved in symptoms of schizophrenia.     

Some central pharmacological effects of (+)- and (−)-oxaprotiline

Summary The central action of oxaprotiline (OXA) enantiomers, administered in a single dose, was studied in rats and mice. (+)-OXA and (–)-OXA attenuated reserpine- and apomorphine-induced hypothermia [(+)-OXA in a more potent manner] in mice and reduced the immobility time in the behavioural despair test in rats. Both OXA enantiomers inhibited locomotor activity in mice and rats, and enhanced and prolonged amphetamine- and apomorphine-induced stereotypy in rats. (–)-OXA potentiated the amphetamine hyperactivity in rats, but not in mice. Nomifensine hyperactivity in rats was unaffected by either enantiomer, and locomotor hypoactivity induced by low doses of apomorphine was also unchanged, as was L-DOPA-induced locomotor hyperactivity in mice. Apomorphine-induced climbing in mice was attenuated by (+)-OXA. Clonidine locomotor hypoactivity and hypothermia were unchanged, and clonidine-induced aggressiveness was attenuated by (+)-OXA. Neither OXA enantiomer affected the action of oxotremorine. In some tests the effect of OXA was stronger at 3 h than at 1 h after administration. The above results indicate that both OXA enantiomers—in particular (–)-OXA—increase some dopaminergic behavioural effects in rats.     

The effect of lithium on the locomotor stimulation induced by dependence-producing drugs

Summary The present study was performed to investigate how lithium affects locomotor stimulation induced by dependence-producing drugs such as amphetamine, ethanol and morphine. Acute lithium alone was found to suppress exploratory hyperactivity in mice without affecting basal locomotor activity, further supporting the contention that lithium has a neurolept-like behavioural profile. Acute lithium pretreatment suppressed locomotor stimulation in mice induced by all the dependence-producing drugs in a dose-dependent manner. Locomotor stimulation seen after amphetamine and ethanol appeared to be more suppressed by lithium than that seen after morphine. Taken together with the finding that lithium had no effect on apomorphine-clonidine-induced locomotor stimulation after elimination of presynaptic activity the present data suggest that the suppressive effect of lithium is mediated via presynaptic catecholaminergic mechanisms.     

NMDA receptor antagonists acting at the glycineB site in rat models for antipsychotic-like activity

Several partial agonist and full antagonists acting at the glycine site of the NMDA receptors were tested for potential antipsychotic-like properties in rats. As models, amphetamine- and phencyclidine (PCP)-induced locomotor activation in the open field and PCP-induced impairment of prepulse inhibition of the acoustic startle response were employed. In the open field test, partial agonists, D-cycloserine failed to show any effect, aminocyclopropane carboxylic acid (ACPC) enhanced the action of PCP (but not that of amphetamine) and R(+)HA-966 attenuated the locomotor activation produced by both amphetamine and PCP. Both full glycineB antagonists, L-701,324 and MRZ 2/576 attenuated the action of amphetamine and PCP but at the doses that also produce transient behavioural inhibition in naive animals. A competitive NMDA receptor antagonist CGP 39551 was ineffective. In the prepulse inhibition test neither L-701,324 nor MRZ 2/576 changed sensorimotor gating in naive animals nor attenuated the disrupting effects of PCP. The present data do not support antipsychotic profile of glycineB full antagonists. However, psychotomimetic potential of glycineB antagonists seems to be low.     

Differential role of serotonin projections from the dorsal and median raphe nuclei in phencyclidine-induced hyperlocomotion and fos-like immunoreactivity in rats

Altered brain serotonin activity is implicated in schizophrenia. We have previously shown differential involvement of serotonergic projections from the dorsal or median raphe nucleus in phencyclidine‐induced hyperlocomotion in rats, a behavioral model of aspects of schizophrenia. Here we further investigated the effects of serotonergic lesions of the raphe nuclei on phencyclidine‐induced hyperlocomotion by parallel assessment of Fos‐like immunoreactivity (FLI), a marker of neuronal activation in the brain. Male Sprague‐Dawley rats were anesthetized with pentobarbitone and stereotaxically microinjected with 5 μg of the serotonergic neurotoxin, 5,7‐dihydroxytryptamine (5,7‐DHT), into either the dorsal raphe (DRN) or median raphe nucleus (MRN). Two weeks after the surgery, rats with lesions of the MRN, but not those with lesions of the DRN, showed significant enhancement of the hyperlocomotion induced by injection of 2.5 mg/kg of phencyclidine. Rats with MRN lesions also showed significantly higher levels of FLI in the polymorphic layer of the dentate gyrus in the dorsal hippocampus (PoDG) when compared with sham‐operated controls. Rats with lesions of the DRN showed significantly higher levels of FLI in the nucleus accumbens (NAcc). These results indicate that FLI in the PoDG, but not the NAcc, correlates with enhanced phencyclidine‐induced locomotor hyperactivity in MRN‐lesioned rats. These results support our previous studies suggesting a role of serotonergic projections from the MRN to the dorsal hippocampus in some of the symptoms of schizophrenia. Synapse, 2012. © 2012 Wiley Periodicals, Inc.     

Hippocampal mediation of raphe lesion- and PCPA-induced hyperactivity in the rat.

These experiments provide a direct test of the hypothesis that median raphe lesion- or PCPA-induced hyperactivity in the rat is mediated specifically by the hippocampus. Previous studies had shown that a marked depletion of hippocampal serotonin accompanied median lesion-induced hyperactivity. In the present studies, aspiration of the anterodorsal hippocampus of adult male rats prior to median raphe lesions or PCPA administration abolished the ability of both of these treatments to produce locomotor hyperactivity in animals chronically housed in tilt cages. Control lesions of the overlying dorsal cortex and corpus callosum were ineffective in blocking the hyperactivity produced by these two treatments. The possibility that serotonin depletion-induced hyperactivity was dependent on the pituitary was excluded by the fact that PCPA effectively elevated the activity of hypophysectomized rats. These data indicate that serotonin depletion-induced hyperactivity in the rat is mediated by the hippocampus.     

Possible involvement of serotonergic neurons in the reduction of locomotor hyperactivity caused by amphetamine in neonatal rats depleted of brain dopamine

This experiment attempted to determine the mechanism by which amphetamine reduces locomotor hyperactivity in neonatal rats given brain dopamine (DA)-depleting 6-hydroxydopamine (6-OHDA) injections. Brain DA neurons were destroyed selectively in neonatal rats by intraventricular (i.v.t.) injections of 6-OHDA following desmethylimipramine (DMI) pretreatment. Control rats received DMI and i.v.t. injections of the 6-OHDA vehicle solution. Rats given the 6-OHDA treatment displayed 7-fold increases in locomotor activity compared to controls during days 16–55 of life. Throughout this period, amphetamine (1 mg/kg) reduced locomotor hyperactivity in 6-OHDA-treated rats but increased locomotor activity in control rats. The reduction of hyperactivity caused by amphetamine (0.5–4 mg/kg) was dose-related and was not accompanied by stereotyped behavior. Like amphetamine, methylphenidate (4 mg/kg) reduced locomotor hyperactivity in rats given 6-OHDA. The DA antagonist, spiroperidol (50–200 μg/kg) failed to attenuate the hyperactivity-reducing effect of amphetamine in 6-OHDA-treated rats at doses which abolished the stimulant effect of amphetamine in control rats. However, the serotonin antagonist methysergide (0.5–4 mg/kg) produced dose-dependent antagonism of the effect of amphetamine in 6-OHDA-treated rats. Pretreatment with propranolol (5 mg/kg), phentolamine (5 mg/kg), atropine (0.5 mg/kg) or naloxone (10 mg/kg) failed to alter the reduction in locomotor hyperactivity caused by amphetamine. The serotonin releasing agent, fenfluramine (3 mg/kg), and the serotonin agonist, quipazine (0.5–4 mg/kg), both reduced locomotor hyperactivity in 6-OHDA-treated rats while not altering locomotion in control rats. These results confirm previous observations that amphetamine reduces locomotor hyperactivity caused by neonatal 6-OHDA administration and suggest that this effect is mediated by increased serotonergic neurotransmission.     

Elevated serotonin is involved in hyperactivity but not in the paradoxical effect of amphetamine in mice neonatally lesioned with 6-hydroxydopamine

The neonatal lesion with 6-hydroxydopamine (6-OHDA) in rodents induces juvenile hyperactivity and paradoxical hypolocomotor response to psychostimulants, in striking contrast to what is observed when similar lesions are carried out in adults. The early disruption of central dopaminergic pathways is followed by increased striatal serotonin (5-HT) contents although the functional role of this neurodevelopmental adaptation remains unclear. The aim of the present study is to investigate the participation of this neurochemical imbalance in the main behavioral phenotypes of this model. To this end, mice received a neonatal administration of 6-OHDA that induced an 80% striatal dopamine depletion together with 70% increase in 5-HT. Serotoninergic hyperinnervation was evidenced further by increased [(3)H] citalopram autoradiographic binding and 5-HT transporter immunohistochemistry in striatal sections. To investigate whether elevated 5-HT was implicated in hyperactivity, we treated control and 6-OHDA neonatally lesioned mice with the selective irreversible tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA) to induce 5-HT depletion. Normalization of striatal 5-HT in 6-OHDA neonatally lesioned mice to control levels reversed hyperactivity to normal locomotor scores, whereas the same extent of 5-HT depletion did not affect spontaneous locomotor activity of control mice. In turn, the paradoxical response to amphetamine in neonatal DA-depleted mice was not prevented by PCPA treatment. Taken together, our results suggest that the increased striatal 5-HT that follows neonatal DA depletion is involved in hyperlocomotor behavior but not in the paradoxical calming response to amphetamine observed in this mouse model.     

Stimulation of postsynaptic alpha1b- and alpha2-adrenergic receptors amplifies dopamine-mediated locomotor activity in both rats and mice

Recent experiments have shown that mice lacking the alpha1b-adrenergic receptor (alpha1b-AR KO) are less responsive to the locomotor hyperactivity induced by psychostimulants, such as D-amphetamine or cocaine, than their wild-type littermates (WT). These findings suggested that psychostimulants induce locomotor hyperactivity not only because they increase dopamine (DA) transmission, but also because they release norepinephrine (NE). To test whether NE release could increase DA-mediated locomotor hyperactivity, rats were treated with GBR 12783 (10 mg/kg), a specific inhibitor of the DA transporter, and NE release was enhanced with dexefaroxan (0.63-10 mg/kg), a potent and specific antagonist at alpha2-adrenergic receptors. Dexefaroxan increased the GBR 12783-mediated locomotor response by almost 8-fold. The role of alpha1b-ARs in this effect was then verified in alpha1b-AR KO mice: whereas dexefaroxan (1 mg/kg) doubled locomotor hyperactivity induced by GBR 12783 (14 mg/kg) in WT mice, it decreased it by 43% in alpha1b-AR KO mice. Finally, to test whether this latter inhibition was related to the occupation of alpha2-adrenergic autoreceptors or of alpha2-ARs not located on noradrenergic neurons, effects of dexefaroxan on locomotor hyperactivity induced by D-amphetamine (0.75 mg/kg) were monitored in rats depleted in ascending noradrenergic neurons. In these animals dexefaroxan inhibited by 25-70% D-amphetamine-induced locomotor hyperactivity. These data indicate not only that the stimulation of alpha1b-ARs increases DA-mediated locomotor response, but also suggest a significant implication of postsynaptic alpha2-ARs. Involvement of these adrenergic receptor mechanisms may be exploited in the therapy of Parkinson's disease.     

Lack of morphine-induced hyperactivity in C57BL/6 mice following striatal kainic acid lesions

Bilateral injection of kainic acid (0.15 micrograms/0.3 microliters) into the striatum (caudatus/putamen) of C57BL/6 mice prevented stimulation of locomotor activity by morphine (20 mg/kg, i.p.). This effect was specific to morphine since mice with the same lesion did not show any impairment of amphetamine (2 mg/kg)-induced locomotor hyperactivity. Histological inspections showed neuron damage also in the nucleus accumbens, while hippocampus was not damaged by kainic acid. Moreover, mice with kainic acid lesions in the hippocampus were more stimulated by morphine, compared with the morphine-injected sham lesion group. The results, which suggest the existence of non-catecholaminergic mediations in the locomotor effects of morphine, are discussed in terms of opioid systems in the brain.     

Behavioural alterations relevant to developmental brain disorders in mice with neonatally induced ventral hippocampal lesions

Neonatal lesioning of the ventral hippocampus (vHc) in rats has served as a useful heuristic animal model to elucidate neurodevelopmental mechanisms of schizophrenia (SCZ). In the current study we have established that this procedure can be applied to model SCZ symptomatology in mice. Neonatal mice (postnatal day 6) were anaesthetised by hypothermia and electrolytic lesions of the vHc were induced. We observed locomotor hyperactivity at prepubertal and adult age and hypersensitivity to amphetamine. Furthermore, working memory deficits were observed in Y-maze (spontaneous alternation) and T-maze (exploration of a novel arm) test protocols. Decreased anxious behaviour in the elevated plus maze and increased sociability were also observed. These changes were dependent on lesion size. No differences were observed in prepulse inhibition of the startle reflex, latent inhibition, spatial memory (Morris water maze), problem solving capacities (syringe puzzle) and ability to discriminate between different unfamiliar mice. The presented findings might further help to identify neurobiological mechanisms of neurodevelopmental disorders.     

Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum.

Eight mug of 6-hydroxydopamine (6-OHDA) injected bilaterally into the nucleus accumbens septi (NAS) or the caudate nucleus of the rat resulted in 79% and 50% depletion of endogenous dopamine (DA) at these respective sites. Fourteen days after the injection a low dose of amphetamine failed to induce the characteristic locomotor response in the NAS-lesioned rats but did so in the caudate-lesioned animals. By contrast the caudate lesion, but not the NAS lesions, abolished intense forms of stereotyped behaviour induced by higher doses of amphetamine. Both lesioned groups exhibited supersensitivity to the dopamine agonist, apomorphine; the NAS group showed enhanced locomotor activity and the caudate group enhanced stereotyped behaviour. The block of amphetamine locomotion and the enhanced response to apomorphine were maximal around 14 days after the operation and gradually attenuated up to 90 days. Theer is evidence that remaining DA levels in the NAS are greater at 90 than at 14 days postoperatively. Thus recovery of behavioural effects correlated with an increase in the remaining levels of DA in the NAS.     

When injected into the fimbria-fornix/cingular bundle, not in the raphe, 5,7-dihydroxytryptamine prevents amphetamine-induced hyperlocomotion

The locomotor effects of acute amphetamine treatment (1 mg/kg, i.p.) were assessed in Long-Evans rats after 5,7-dihydroxytryptamine (5, 7-DHT) injections into the fimbria-fornix/cingular bundle (FiFx/CB; 4 microg/side), or the dorsal and median raphe (Raphe; 10 microg). In control rats, amphetamine induced a significant increase of home-cage activity for about 2 h. This effect was similar in Raphe rats, but was absent in FiFx/CB rats. The raphe lesions reduced serotonin concentrations by 50% in the dorsal hippocampus, 75% in the ventral hippocampus and 58% in the fronto-parietal cortex. After FiFx/CB lesions, the reduction amounted 50, 61 and only 25%, in each of these regions, respectively. In the fronto-partietal cortex, dopamine concentration was significantly decreased in Raphe (-27%) and FiFx/CB rats (-65%). The results suggest that a serotonergic denervation of the hippocampus by injections of 5,7-DHT into the FiFx/CB pathways hampers the stimulating effects of amphetamine on locomotor activity. This effect might be related to the reduced dopaminergic tone in the fronto-parietal cortex.     

A possible physiological role for cerebral tetrahydroisoquinolines

Tetrahydroisoquinolines present in the mammalian brain, 1,2,3,4-tetrahydroisoquinoline (TIQ) and salsolinol, suspected to cause neurodegeneration leading to Parkinson's disease, were investigated to find their possible physiological role. To this aim their behavioral and receptor effects induced after a single dose were tested in mice and rats. Both compounds do not affect significantly the basal locomotor activity, very effectively block hyperactivity induced by apomorphine (rats) and amphetamine (mice), only partially block hyperactivity induced by scopolamine, do not affect locomotor stimulation induced by cocaine, and strongly augment the running fit induced by morphine (mice). They do not produce extrapyramidal symptoms and do not potentiate haloperidol-induced catalepsy (rats). TIQ and salsolinol do not displace antagonists of several receptors (including D(1) and D(2)) from their binding sites, but displace the agonists of Alpha(2)-adrenoceptors, [(3)H]clonidine and of dopamine receptors, [(3)H]apomorphine. The results indicate that salsolinol and TIQ act as specific antagonists of agonistic conformation of dopamine receptors, and owing to that may play a role of endogenous feed-back regulators of the dopaminergic system. Those properties make tetrahydroisoquinolines potential antidopaminergic drugs devoid of extrapyramidal effects, with possible application in substance addiction disorder as anti-craving agents.     

Consequences of amygdala kindling and repeated withdrawal from ethanol on amphetamine-induced behaviours

It has been shown previously that chronic ethanol treatment in mice leads to accelerated behavioural sensitization to psychomotor stimulants [Manley & Little (1997) J. Pharmacol. Exp. Ther., 281, 1330-1339], whilst repeated experience of ethanol withdrawal sensitizes pathways underlying seizure activity (Becker & Hale (1993) Alcohol Clin. Exp. Res., 17, 94-98]. The aim of the current experiment was to investigate the consequences of repeated withdrawal from ethanol on amphetamine-induced behaviours in the rat and compare this with animals with electrical kindling of the amygdala, a procedure that has been shown to enhance alcohol withdrawal seizures [Pinel et al. (1975) Can. J. Neurol. Sci., 2, 467-475]. For the kindling experiments, electrodes were surgically implanted in the left basolateral amygdala and were stimulated daily at the afterdischarge threshold until a criterion of three consecutive stage 5 seizures was reached. Fully kindled rats showed a marginally significant reduction in sensitivity to the locomotor stimulant effects of acute amphetamine compared with sham and partially kindled rats which had experienced subthreshold stimulation of the amygdala. Sham and partially kindled rats sensitized readily to the locomotor activating effects of amphetamine (0.125 mg/kg) following repeated treatments, but the fully kindled rats did not. Fully kindled rats also failed to show place preference conditioning to amphetamine (0.5 mg/kg). Rats, withdrawn three times from chronic ethanol (liquid-diet), kindled more quickly to PTZ (30 mg/kg, i.p.) than rats with the same overall exposure to ethanol (24 days) followed by a single withdrawal or control animals. However, there was no difference in the locomotor stimulating effects of acute amphetamine (0.25-1 mg/kg, i.p.), the rate of sensitization to amphetamine (0.125 mg/kg, i.p.) or amphetamine induced conditioned place preference (1 mg/kg, i.p.). These observations suggest that, in rats, repeated withdrawal from a relatively mild chronic ethanol treatment modulates neuronal systems that may also be involved in PTZ-induced kindling but not those involved in either the acute stimulant effects of amphetamine or behavioural sensitization or appetitive conditioning following repeated amphetamine administration. Behavioural changes following amygdala kindling differed from those following repeated ethanol withdrawal, suggesting that withdrawal kindling from a mild ethanol treatment differs in its effects from amygdala kindling.     

Differential involvement of 5-HT projections within the amygdala in prepulse inhibition but not in psychotomimetic drug-induced hyperlocomotion

While there is abundant evidence for a role of 5-HT and the amygdala in anxiety and depression, the role of 5-HT in this brain region in schizophrenia is less well understood. We therefore examined the effects of local 5-HT depletion in the amygdala on psychotomimetic drug-induced locomotor hyperactivity and prepulse inhibition, two animal model of aspects of schizophrenia. Pentobarbital-anaesthetized (60 mg/kg, i.p.) male Sprague-Dawley rats were stereotaxically micro-injected with 0.5 microl of a 5 microg/mul solution of the 5-HT neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into either the basolateral (BLA) or central nucleus of amygdala (CeN). Two weeks after the surgery, rats with BLA lesions did not show changes in either psychotomimetic drug-induced locomotor hyperactivity or prepulse inhibition. In contrast, rats with CeN lesions showed significant disruption of prepulse inhibition, but no changes in psychotomimetic drug-induced locomotor hyperactivity. Neurochemical analysis and autoradiographic labelling of 5-HT transporter sites showed that a good degree of anatomical selectivity was obtained. Following administration of 5,7-DHT into the amygdala, the concentration of 5-HT was significantly reduced. Similarly, 5-HT transporter autoradiographs showed differential and selective lesions of 5-HT innervation in targeted subregions of the amygdala. These results provide evidence for differential involvement of 5-HT projections within the amygdala in prepulse inhibition but not locomotor hyperactivity. Thus, the present study supports the view that 5-HT in the amygdala may be involved in aspects of schizophrenia and a target for antipsychotic drug action.     

Importance of animal models in schizophrenia research

OBJECTIVE: This review aims to summarize the importance of animal models for research on psychiatric illnesses, particularly schizophrenia. METHOD AND RESULTS: Several aspects of animal models are addressed, including animal experimentation ethics and theoretical considerations of different aspects of validity of animal models. A more specific discussion is included on two of the most widely used behavioural models, psychotropic drug-induced locomotor hyperactivity and prepulse inhibition, followed by comments on the difficulty of modelling negative symptoms of schizophrenia. Furthermore, we emphasize the impact of new developments in molecular biology and the generation of genetically modified mice, which have generated the concept of behavioural phenotyping. CONCLUSIONS: Complex psychiatric illnesses, such as schizophrenia, cannot be exactly reproduced in species such as rats and mice. Nevertheless, by providing new information on the role of neurotransmitter systems and genes in behavioural function, animal 'models' can be an important tool in unravelling mechanisms involved in the symptoms and development of such illnesses, alongside approaches such as post-mortem studies, cognitive and psychophysiological studies, imaging and epidemiology.     

Blockage of amphetamine induced motor stimulation and stereotypy in the adult rat following neonatal treatment with 6-hydroxydopamine

6-Hydroxydopamine was administered intraventricularly to neonatal rats in order to rear adults with severe catecholamine depletions. The functional integrity of the remaining amine systems was examined in the adult rats by assessing the behavioural responses to pre- and postsynaptic pharmacological manipulations. The locomotor stimulation and stereotypy response tod-amphetamine were blocked in these animals. The dopaminergic receptors in the striatum were supersensitive, as evidenced by an enhanced stereotypy response to apomorphine, suggesting that the blockage of the stereotypy response to amphetamine was presynaptic in origin. Regional, biochemical assay showed that there was an almost complete destruction of the dopaminergic input to the striatum, and a less complete destruction of the forebrain noradrenergic systems. Clonidine stimulated locomotor activity in control rats but not in the 6-OH-DA treated rats further suggesting the probable primacy of dopaminergic systems for the mediation of the locomotor response to amphetamine.