Chronic low dose risperidone and clozapine alleviate positive but not negative symptoms in the rat neonatal ventral hippocampal lesion model of schizophrenia

Rationale The rat neonatal ventral hippocampal (VH) ibotenic lesion model has been proposed as a developmental model of schizophrenia, based on evidence that it encompasses aspects of the disorder including psychomotor agitation (hyperactivity), deficits in prepulse inhibition (PPI), and deficits in social interaction (SI), measures presumed to reflect positive symptoms, sensory gating deficits and negative symptoms, respectively. However, validation of the model as a predictive pharmacological screening tool has been minimal.Objective Determine the effects of a chronic 3-week low dose treatment of clozapine or risperidone on locomotor hyperactivity, PPI and SI in lesioned and control rats.Results Both clozapine, 2.5 mg/kg per day IP and risperidone, 0.1 mg/kg per day IP, reversed lesion-induced locomotor hyperactivity; however, the compounds also decreased locomotor activity in the non-lesioned controls. Clozapine 2.5 mg/kg per day and risperidone 0.1 mg/kg per day significantly attenuated lesion-induced PPI deficits. Neither compound induced a significant attenuation of lesion-induced SI deficits. In order to see if SI deficits required a higher dose of an antipsychotic, the dose of clozapine was increased to 4 mg/kg per day; however this dose induced such marked decreases in the activity and startle responses in the control rats, i.e. up to 74% decrease, that the effects on the lesioned rats could not be adequately interpreted.Conclusions These data add further support to the neonatal VH lesion model as a predictive pharmacological screening assay for identifying compounds effective in the treatment of positive symptoms of schizophrenia. However, the usefulness of the model in detecting compounds effective in treating negative symptoms of schizophrenia is still in question.     

Enhanced alpha1 adrenergic sensitivity in sensorimotor gating deficits in neonatal ventral hippocampus-lesioned rats

Neonatal ventral hippocampus (nVH) lesion in rats is a widely used animal model of schizophrenia due to the predominantly post-pubertal emergence of many schizophrenia-like behaviours. Our previous studies have shown increased ligand binding of alpha1 adrenergic receptors (AR) in the frontal cortex of post-pubertal, but not pre-pubertal, nVH-lesioned rats, compared to sham-lesioned control rats. Moreover, pretreatment with the alpha1 adrenergic receptor antagonist prazosin reversed amphetamine-induced hyperlocomotion in controls, but failed to do so in lesioned animals. This led to our hypothesis that nVH lesions may lead to post-pubertal hyperactivity of alpha1 adrenergic receptors. In order to test the functional relevance of alpha1 adrenergic hyperactivity to schizophrenia-like behaviours of nVH-lesioned animals, we conducted prepulse inhibition (PPI) studies in post-pubertal (postnatal days 56-120) sham and lesioned animals in response to systemic injections of alpha1 adrenergic receptor antagonist and agonist, prazosin and cirazoline, respectively. Our results show that PPI deficits in nVH-lesioned animals were reversed with prazosin treatment, without a significant effect on PPI in sham animals. Further, at various doses, cirazoline had a significantly greater PPI disruptive effect in nVH-lesioned animals than in sham animals. Together, these results suggest that nVH-lesioned animals show a hyperactive alpha1 adrenergic receptor system that may mediate sensorimotor gating abnormalities reported in these animals.     

Stereoselective effects of methylphenidate on motor hyperactivity in juvenile rats induced by neonatal 6-hydroxydopamine lesioning

RATIONALE: The psychostimulant dl-threo-methylphenidate is commonly used to treat attention deficit-hyperactivity disorder (ADHD). Consistent with its effects in ADHD patients, racemic methylphenidate antagonizes behavioral hyperactivity in several animal models of ADHD, including juvenile rats with neonatal 6-hydroxydopamine (6-OHDA) lesions of forebrain dopamine projections. The enantiomers of methylphenidate differ markedly in stimulant potency but have not been compared in the 6-OHDA lesion model. OBJECTIVE: Locomotor-inhibiting effects of methylphenidate enantiomers were compared in 6-OHDA-lesioned rats to test the hypothesis that d-methylphenidate is more potent than dl- and l-methylphenidate. METHODS: Selective dopamine lesions were made using 6-OHDA (100 microg, intracisternal, IC) on postnatal day (PD) 5 after desipramine (25 mg/kg, SC) pretreatment to protect noradrenergic neurons. Effects of d-, l- and dl-threo-methylphenidate on locomotor activity of lesioned and sham control rats were quantified at PD 23-27. RESULTS: Lesioning yielded robust motor hyperactivity at PD 23-27. Both d- and dl-methylphenidate stimulated locomotor activity in intact rats, and inhibited activity in lesioned rats. l-Methylphenidate did not affect locomotor activity in either lesioned rats or controls. d-Methylphenidate (ED(50)=1.66 mg/kg) was 3.3 times more potent than dl-methylphenidate (ED(50)=5.45 mg/kg) in reducing locomotor hyperactivity in lesioned rats. In addition, pretreatment of lesioned rats with l-methylphenidate significantly reduced the motor inhibiting effects of d-methylphenidate. CONCLUSIONS: The more active enantiomer, as predicted, was d-methylphenidate, but the l-enantiomer interfered with its effects, suggesting that clinical potency of d-methylphenidate may be more than twice that of the racemate.     

Hyperresponsiveness to phencyclidine in animals lesioned in the amygdala on day 7 of life. Implications for an animal model of schizophrenia.

Phencyclidine (PCP) has been described to exacerbate psychotic symptoms in patients suffering from schizophrenia. In rats, PCP, dose-dependently, induces hyperactivity, stereotyped behaviour and social isolation, postulated to represent the positive (hyperactivity, stereotypy) and negative (social isolation) symptoms of schizophrenia. Based on previous studies, ibotenic acid lesions in the amygdala on day 7 of life have been proposed as an animal model of psychiatric neurodevelopmental disorders like schizophrenia. The purpose of the present study was to determine whether the responsiveness to PCP on locomotor activity in animals lesioned in the amygdala on day 7 of life is different from the response to this drug in sham-operated animals. The effect of graded doses of PCP on behaviour was assessed in a small open field. Animals lesioned in the amygdala on day 7 of life appeared to be hyperresponsive to PCP compared to sham-operated animals. The hyperresponsiveness to PCP in rats lesioned in the amygdala on day 7 of life further contributes to the validation of this putative animal model of schizophrenia.     

The effects of kainic acid lesions on locomotor responses to haloperidol and clozapine

 Spontaneous and amphetamine-elicited locomotor activity in rats is reduced by most clinically effective antipsychotic drugs. We have recently demonstrated that intracerebroventricular infusion of kainic acid (KA), which produces cell loss in the hippocampus and other limbic-cortical brain regions, increases spontaneous and amphetamine-elicited locomotion. The present study determined if KA lesions alter the suppressive effects of the antipsychotic drugs, haloperidol and clozapine, on spontaneous and amphetamine-elicited locomotor behavior. Young adult male rats (70 days of age) received intracerebroventricular infusions of vehicle or KA, which produced hippocampal pyramidal cell loss in each rat and more variable cell loss or gliosis in the amygdala, piriform cortex, and laterodorsal thalamus. Thirty days post-surgery, lesioned and control rats were tested once a week for locomotor responses to drug treatments. As observed previously, spontaneous locomotor activity and hyperactivity elicited by amphetamine (1.50 mg/kg SC) were greater in lesioned animals than controls. In addition, the level of spontaneous activity and/or amphetamine-elicited hyperlocomotion observed in lesioned rats after haloperidol treatment (0.13, 0.35, or 1.50 mg/kg SC) was greater than that found in controls. Locomotor responses to low (6.30 mg/kg) and moderate doses of clozapine (20 mg/kg) were similar in lesioned and control rats, although lesioned rats were more active than controls following the administration of a high dose of clozapine (30 mg/kg). These data indicate that the hyperactivity associated with limbic-cortical lesions may be insensitive to reversal by haloperidol, yet uniquely sensitive to suppression by clozapine. Received: 1 April 1997/Final version: 6 August 1997     

Differential role of serotonergic projections arising from the dorsal and median raphe nuclei in locomotor hyperactivity and prepulse inhibition.

While an involvement of brain serotonin systems in schizophrenia has been suggested by many studies, the relative role of different serotonergic projections in the brain remains unclear. We therefore examined the effects of selective brain serotonin depletion on psychotropic drug-induced locomotor hyperactivity and prepulse inhibition, two animal models of aspects of schizophrenia. Pentobarbital-anesthetized (60 mg/kg, i.p.) male Sprague-Dawley rats were stereotaxically microinjected with 1 microl of a 5 microg/microl solution of the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into either the dorsal or median raphe nucleus. At 2 weeks after the surgery, rats with dorsal raphe lesions did not show changes in psychotropic drug-induced locomotor hyperactivity, but displayed partial disruption of prepulse inhibition. In contrast, rats with median raphe lesions showed significant enhancement of phencyclidine-induced, but not amphetamine-induced locomotor hyperactivity and a marked disruption of prepulse inhibition. These results provide evidence for differential involvement of serotonergic projections in locomotor hyperactivity and prepulse inhibition. This study may help to explain the role of different serotonin projections in the brain in the pathophysiology of schizophrenia.     

Spontaneous exploration of a 6-arm radial tunnel maze by basal forebrain lesioned rats: effects of the benzodiazepine receptor antagonist β-carboline ZK 93 426

Nine days following ibotenic acid induced basal forebrain lesions or a sham-operation, rats were allowed to explore an automated six-arm radial tunnel maze. From each session, several measures of locomotor and exploratory activity were registered. Lesioned and sham-operated animals were treated with either the benzodiazepine receptor antagonist -carboline ZK 93 426 (5 mg/kg; IP) or vehicle (Cremofor EL 10% in saline; IP; n=10 for each group). Treatment was carried out 30 min before each session during acquisition (seven sessions) and reversals of the maze configuration (seven session). Eight days following the 14th session, the animals were retested without any further drug treatment. The main results suggest that the lesion resulted in locomotor hyperactivity, an increase in the number of blind arm entries, and of choice stereotypy. Treatment with ZK 93 426 attenuated the lesion-induced alterations of locomotor and exploratory activities. During the retest, the lesioned, previously vehicle-treated rats revisited arms which they had already explored during this session more frequently than the lesioned, previously ZK-treated rats; the latter group did not differ from the sham-lesioned controls. It is concluded that basal forebrain lesioned animals explored the tunnel maze less efficiently than sham-lesioned controls and that the lesioned animals benefited from the treatment with ZK 93 426. Although the specificity of the lesion in terms of destruction of cholinergic neurons remains unsettled, and although the psychological significances of the behavioral measures obtained from the tunnel maze are not yet fully understood, these results suggest that antagonists or partial inverse agonists at the benzodiazepine receptor may be able to normalize basal forebrain lesion-induced behavioral alterations.     

Post-pubertal adrenergic changes in rats with neonatal lesions of the ventral hippocampus

Lesions of the ventral hippocampus (VH) in neonatal rats result in post-pubertal alterations in a number of cognitive, social and motor behaviors that bear some analogy to schizophrenia. Increased sensitivity to stress and psychostimulants and prefrontal functional changes in the lesioned animals suggest an involvement of the mesocorticolimbic dopamine (DA) system. DA and norepinephrine (NE) interact in a number of ways in the medial prefrontal cortex (mPFC) to influence each other's functions. In order to assess the role of adrenergic system in the behavioral responses of neonatal VH (nVH) lesioned animals, we first examined cortical and subcortical bindings of alpha-1 and alpha-2 adrenergic receptors using [3H]-prazosin and [3H]-rauwolscine respectively, and the norepinephrine transporter (NET) using [3H]-nisoxetine. Sprague-Dawley rat pups, at post-natal day (PD) 7, received bilateral injections of ibotenic acid in the VH and were sacrificed pre (PD35)- and post (PD56)-pubertally. A significant increase in [3H]-prazosin binding was observed in the frontal and cingulate cortices of lesioned rats at PD56 without any significant change in the caudate putamen or nucleus accumbens. No significant difference was seen in [3H]-rauwolscine binding. A significant upregulation of NET binding was observed in subregions of the PFC and nucleus accumbens of PD56 lesioned rats. The functional relevance of changes in adrenergic markers on amphetamine-induced locomotor activity was examined by pre-treatment of PD56 rats with prazosin, an alpha-1 receptor antagonist. Prazosin at doses of 1.0 or 2.0 mg/kg ip significantly reduced amphetamine-induced locomotion in sham but not in PD56 lesioned animals. Taken together, these results suggest that alterations in prefrontal alpha-1 receptors likely contribute to altered behavioral responses observed in post-pubertal VH lesioned rats.     

Blockade of dopamine D₃ but not D₂ receptors reverses the novel object discrimination impairment produced by post-weaning social isolation: implications for schizophrenia and its treatment

Dopamine D? receptors are densely expressed in mesolimbic projection areas, and selective antagonists enhance cognition, consistent with their potential therapeutic use in the treatment of schizophrenia. This study examines the effect of dopamine D? vs. D? receptor antagonists on the cognitive impairment and hyperactivity produced by social isolation of rat pups, in a neurodevelopmental model of certain deficits of schizophrenia. Three separate groups of male Lister hooded rats were group-housed or isolation-reared from weaning. Six weeks later rats received either vehicle or the dopamine D? selective antagonist, S33084 (0.04 and 0.16 mg/kg), the preferential D? antagonist, S33138 (0.16 and 0.63 mg/kg) or the preferential D? antagonist, L-741,626 (0.63 mg/kg) s.c. 30 min prior to recording; horizontal locomotor activity in a novel arena for 60 min and, the following day, novel object discrimination using a 2-h inter-trial interval. Isolation rearing induced locomotor hyperactivity in a novel arena and impaired novel object discrimination compared to that in group-housed littermates. Both S33084 and S33138 restored novel object discrimination deficits in isolation-reared rats without affecting discrimination in group-housed controls. By contrast, L-741,626 impaired novel object discrimination in group-housed rats, without affecting impairment in isolates. S33084 (0.16 mg/kg), S33138 and, less markedly, L741,626 reduced the locomotor hyperactivity in isolates without attenuating activity in group-housed controls. Selective blockade of dopamine D? receptors reverses the visual recognition memory deficit and hyperactivity produced by isolation rearing. These data support further investigation of the potential use of dopamine D? receptor antagonists to treat schizophrenia.     

Glucocorticoids modulate behavioral effects induced by dopaminergic agonists in rats

Studies showing the presence of glucocorticoids, and their binding sites in the central nervous system indicate that these hormones may affect central neurotransmission. Both, dopaminergic brain system and glucocorticoids are considered to be involved in certain psychopathological conditions in humans, including depression, addiction or schizophrenia. The present study aimed to investigate the influence of glucocorticoids on dopamine agonists-induced stereotyped behavior and locomotor hyperactivity in rats. The results of the experiment demonstrate that prior to administration of prednisolone (4, 6, 10 or 20 mg/kg) or dexamethasone (4 or 8 mg/kg) intensified and prolonged the stereotypy induced by apomorphine (1 mg/kg sc) or amphetamine (2 mg/kg ip). The effect of dexamethasone was more potent. Amphetamine (0.4 mg/kg)- or amantadine (50 mg/kg)-induced locomotor hyperactivity was significantly reduced in rats pretreated with dexamethasone at a dose of 8 mg/kg or 4 mg/kg. Our observations suggest that exogenous glucocorticoids may enhance the activity of the dopaminergic agonists in the striatum but reduce it in the mesolimbic system of rats.     

Effects of amphetamine and apomorphine on locomotor activity after kainic acid lesion of the nucleus accumbens septi in the rat

Kainic acid injections into the nucleus accumbens in rats induced severe loss of neuronal perikarya and the presence of gliosis in its vicinity, without affecting more distant areas. Spontaneous locomotor activity was elevated in the lesioned rats. After a low dose of d-amphetamine (1.5 mg/kg) no significant differences in locomotor activity were found between lesioned and sham-operated rats, while the increase in locomotor activity normally induced by a moderate dose of apomorphine (1 mg/kg) was blocked in lesioned rats. These results indicate that although dopamine receptors on the nucleus accumbens neurons are involved in the mechanisms mediating locomotor behaviour, the locomotor stimulant effect of d-amphetamine is not exclusively dependent on intra-accumbens dopaminergic activity.     

The mGlu2 but not the mGlu3 receptor mediates the actions of the mGluR2/3 agonist, LY379268, in mouse models predictive of antipsychotic activity

Rationale Group II metabotropic glutamate receptors (mGluRs) comprise the mGluR2 and mGluR3 subtypes, the activation and modulation of which has been suggested to be beneficial for treating schizophrenia. Genetic association studies suggest limited association between mGluR2 and schizophrenia but some association between mGluR3 and schizophrenia. Conversely, pre-clinical studies suggest that mGluR2 may be responsible for mediating the antipsychotic activity of mGluR2/3 agonists, although to date, the role of mGluR3 has not been specifically assessed. Objectives The aim of this study is to use recently generated mGluR3 and mGluR2 knockout mice to investigate which of the group II mGluRs mediates the actions of the mGluR2/3 agonist, LY379268, in two mouse models predictive of antipsychotic activity. Materials and methods LY379268 (0.3–10 mg/kg SC), phencyclidine (PCP; 1–5 mg/kg IP), and amphetamine 1–10 mg/kg IP) were assessed on locomotor activity and behaviour in C57Bl/6J and transgenic mice. LY379268 was then assessed on PCP (5 mg/kg IP)- and amphetamine (2.5 mg/kg IP)-induced hyperactivity and behaviour in C57Bl/6J and transgenic mice. Results PCP (5 mg/kg)-evoked hyperactivity and behavioural alterations, i.e. circling, falling, stereotypy and ataxia, as well as amphetamine (2.5 mg/kg)-evoked hyperactivity, were dose-dependently attenuated by LY379268 (0.3–3 mg/kg) in C57Bl/6J mice. One milligram per kilogram of LY379268 reversed PCP-evoked hyperactivity and behavioural alterations in wild-type (WT) and mGluR3 knockout mice but not in mice lacking mGluR2. Similarly, 3 mg/kg LY379268 reversed amphetamine-evoked hyperactivity in WT and mGluR3 knockout mice but not in mice lacking mGluR2. Conclusion The mGlu2 but not the mGlu3 receptor subtype mediates the actions of the mGluR2/3 agonist, LY379268, in mouse models predictive of antipsychotic activity.     

The role of the substantia nigra in the locomotor stimulant action of amphetamine

1. The electrolytic brain lesion technique was used to evaluate the role of the substantia nigra in the mediation of the locomotor stimulant effect of (+)-amphetamine in the rat. The effect upon the results of variations in strain and basal activity levels of the rats was assessed.2. In the immediate postoperative phase the lesioned animals developed spontaneous stereotyped behaviour patterns which were more intense in rats of initially high basal activity. Activity was depressed at this stage and only that of the low activity animals was stimulated by amphetamine.3. After the 2nd postoperative day rats with lesions of the substantia nigra developed hyperactivity, but this was only maintained in rats initially of low basal activity. During this stage the locomotor stimulant effect of amphetamine (1.0 mg/kg) was apparent and after the 9th postoperative day animals generally displayed an increased sensitivity to the drug effect.4. The involvement of the substantia nigra with the control of locomotor activity is indicated but its integrity would not appear essential for the mediation of the locomotor stimulant effects of amphetamine.     

Increased sensitivity of adolescent spontaneously hypertensive rats, an animal model of attention deficit hyperactivity disorder, to the locomotor stimulation induced by the cannabinoid receptor agonist WIN 55,212-2

Converging evidence points to adolescence as a critical period for the onset of a wide range of neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD) and drug abuse. Spontaneously hypertensive rats (SHR) are generally considered to be a suitable genetic model for the study of ADHD, since they display hyperactivity, impulsivity, poorly sustained attention, cognitive deficits and increased novelty seeking. Despite the high prevalence of ADHD among adolescents, studies using SHR have mainly been performed on adult animals. The aim of the present study was to evaluate the effect of acute intraperitoneal (i.p.) administration of the cannabinoid receptor agonist WIN 55,212-2 (0.25-2.5 mg/kg) on locomotor activity and anxiety-like behavior in male adolescent and adult SHR and Wistar rats using the open field and elevated plus-maze tests. WIN 55,212-2 at doses of 0.25 and 1.25 mg/kg (i.p.) selectively promoted locomotor stimulation in adolescent SHR in the open field, but not in adult SHR or Wistar rats (regardless of age). The effect of WIN 55,212-2 (0.25 mg/kg, i.p.) on locomotion of adolescent SHR was reversed by pretreatment with the selective cannabinoid CB1 receptor antagonist AM 251 (0.25 mg/kg, i.p.). Moreover, although the present doses of WIN 55,212-2 had no effect on anxiety-related behaviors in any of the animal groups evaluated in the open field (central locomotion) or elevated plus-maze (time and entries in open arms), the highest dose of WIN 55,212-2 tested (2.5 mg/kg, i.p.) significantly decreased the number of closed-arm entries (an index of locomotor activity) of adolescent rats of both the Wistar and SHR strains in the elevated plus-maze. The present results indicate strain- and age-related effects of cannabinoids on locomotor activity in rats, extending the notion that adolescence and ADHD represent risk factors for the increased sensitivity to the effects of drugs.     

Neonatal lesions in the amygdala or ventral hippocampus disrupt prepulse inhibition of the acoustic startle response; implications for an animal model of neurodevelopmental disorders like schizophrenia.

Prepulse inhibition of the acoustic startle response is a behavioural tool applied to assess sensorimotor gating processes in humans and rats. Schizophrenic patients show deficits in prepulse inhibition of the acoustic startle response. The animal model of neurodevelopmental disorders such as schizophrenia, as purported in earlier reports and the present study, is based on the assumption that damage to brain structures early in life (on day 7) disrupts brain maturation of structures connected to the damaged areas, measurable by behavioural changes, whereas similar damage later in life (on day 21) does not result in these behavioural changes. Locomotor activity, the acoustic startle response and its prepulse inhibition were investigated in adult rats lesioned in the amygdala or ventral hippocampus on day 7 or 21 of life. The acoustic startle response was increased in animals lesioned in the amygdala on day 7 or 21 of life, but not in animals lesioned in the ventral hippocampus. Prepulse inhibition was impaired and locomotor activity enhanced in animals lesioned in the amygdala or ventral hippocampus on day 7, but not in animals lesioned in these structures on day 21 of life. The results on the acoustic startle response are suggestive of amygdaloid influences on modulation of the acoustic startle response. The effects of early postnatal lesions on prepulse inhibition and locomotor activity are in support of the animal model of neurodevelopmental disorders like schizophrenia.     

GABAB/NMDA receptor interaction in the regulation of extracellular dopamine levels in rodent prefrontal cortex and striatum

Deficits in N-methyl-d-aspartate receptor (NMDAR)-mediated neurotransmission may underlie dopaminergic hyperactivity in schizophrenia. Dysregulation of the GABAergic system has also been implicated. In this study we investigated a role for GABA_B receptors as an intermediate step in the pathway leading from NMDAR stimulation to DA regulation. Since glycine (GLY) has been found to ameliorate treatment resistant negative symptoms in schizophrenia, we treated a group of rats with 16% GLY food for 2 weeks. DA levels in prefrontal cortex (PFC) and striatum (STR) were assessed by dual-probe microdialysis and HPLC-EC in freely moving rats. Infusion of the GABA_B receptor agonists SKF97541 and baclofen into PFC and STR significantly reduced basal DA, an effect that was reversed by the antagonist, CGP52432. In PFC, GABA_B agonists also reduced AMPH-induced DA release following treatment with either 1 or 5 mg/kg AMPH. Similar effects were seen following subchronic glycine treatment in the absence, but not presence of CGP52432 during 5 mg/kg AMPH treatment. In STR SKF97541 decreased only the 1 mg/kg AMPH-induced DA release. Subchronic GLY treatment in STR leads to a significant reduction in basal DA levels, but did not affect AMPH (5 mg/kg)-induced release. Our findings support a model in which NMDA/glycine-site agonists modulate DA release in part through presynaptic GABA_B receptors on DA terminals, with both GABA_B ligands and GLY significantly modulating AMPH-induced DA release. Both sites, therefore, may represent appropriate targets for drug development in schizophrenia and substance abuse disorders.     

Locomotor activity of rats after stimulation of the nucleus locus coeruleus region or after lesion of the dorsal noradrenergic bundle: Effects of clonidine,prazosin and yohimbine

We previously showed in the rat that electrical stimulation of the nucleus locus coeruleus produced, 4 weeks later, a significant increase in the number of ₁ and ₁ in the cerebral cortex. In a parallel pharmacological study, we tested the effects of small doses of clonidine on the locomotor activity of stimulated rats and implanted but not stimulated animals. In stimulated rats only, clonidine had a dual effect: firstly, sedation 30 min after injection, and secondly, hyperactivity which was observed 24 h after injection. In the present study, using the same behavioral paradigm, we tested the effects of small doses of clonidine on the locomotor activity of three groups of rats: stimulated in the locus coeruleus, lesioned in the dorsal noradrenergic bundle and controls. In stimulated rats injected with clonidine, delayed hyperactivity appeared 24 h after the injection, beginning at the smallest dose used (2.5 g/kg). This hyperactivity was not due to the stimulation per se, since it did not appear in stimulated rats injected with the vehicle. In rats with dorsal noradrenergic bundle lesions, this delayed hyperactivity was observed only after a high dose (50 g/kg) of clonidine. In a second experiment, we tested the effect of small doses of prazosin or of yohimbine on the delayed, drug-induced, hyperactivity of stimulated or lesioned rats. In stimulated rats, prazosin (an ₁-adrenoceptor antagonist) suppressed the hyperactivity produced by clonidine. Yohimbine (an ₂-adrenoceptor antagonist) markedly increased the locomotor activity of stimulated rats injected with vehicle. Likewise, in lesioned rats, prazosin suppressed the hyperactivity produced by a dose of 50 g/kg of clonidine. These results are interpreted in relation to the possible role of -adrenoceptors in the regulation of locomotor activity.     

Neonatal exposure to phenobarbital potentiates schizophrenia-like behavioral outcomes in the rat

Previous work has indicated an association between seizures early in life and increased risk of psychiatric disorders, including schizophrenia. However, because early-life seizures are commonly treated with antiepileptic drugs (AEDs) such as phenobarbital, the possibility that drug treatment may affect later-life psychiatric outcomes needs to be evaluated. We therefore tested the hypothesis that phenobarbital exposure in the neonatal rat increases the risk of schizophrenia-like behavioral abnormalities in adulthood. Thus, in this study, we examined the effects of a single acute neonatal exposure to phenobarbital on adult behavioral outcomes in the rat neonatal ventral hippocampal (nVH) lesion model of schizophrenia. We compared these outcomes to those in rats a) without nVH lesions and b) with nVH lesions, without phenobarbital. The tasks used for behavioral evaluation were: amphetamine-induced locomotion, prepulse inhibition, elevated plus-maze, and novel object recognition task. We found that neonatal phenobarbital treatment (in the absence of nVH lesions) was sufficient to disrupt sensorimotor gating (as tested by prepulse inhibition) in adulthood to an extent equivalent to nVH lesions. Additionally, neonatal phenobarbital exposure enhanced the locomotor response to amphetamine in adult animals with and without nVH lesions. Our findings suggest that neonatal exposure to phenobarbital can predispose to schizophrenia-like behavioral abnormalities. Our findings underscore the importance of examining AED exposure early in life as a potential risk factor for later-life neuropsychiatric abnormalities in clinical populations.     

Role of 5-HT(2a) and 5-HT(2B/2C) receptors in the behavioral interactions between serotonin and catecholamine reuptake inhibitors.

Dysfunction of monoamine neurotransmission seems to contribute to such pathopsychological states as depression, schizophrenia, and drug abuse. The present study examined the effects of the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) and antidepressant fluvoxamine on locomotor activity in rats following administration of the catecholamine reuptake inhibitor mazindol. Mazindol (1 mg/kg) did not alter locomotor activity; whereas, fluvoxamine (20 mg/kg) given alone induced a brief period of hypomotility. Hyperactivity was elicited in a dose-related manner when fluvoxamine (5-20 mg/kg) was combined with mazindol (1 mg/kg). The hyperactivity elicited by fluvoxamine (20 mg/kg) plus mazindol (1 mg/kg) was significantly attenuated by the 5-HT(2A) receptor antagonist M100907 (2 mg/kg) and potentiated by the 5-HT(2B/2C) receptor antagonist SB 206553 (2 mg/kg). Neither antagonist significantly altered basal activity. The hyperactivity evoked by the combination of fluvoxamine and mazindol seems to be mediated in part by 5-HT(2A) receptors; whereas, 5-HT(2B/2C) receptors may serve to limit this effect. Thus, the balance of activation between 5-HT(2A) and 5-HT(2B/2C) receptors seems to contribute to the expression of locomotor hyperactivity evoked via combination of a 5-HT and a catecholamine reuptake inhibitor. A disruption in this balance may contribute to the expression of affective disorders, schizophrenia, and drug abuse.     

Chronic benzylpiperazine (BZP) exposure produces behavioral sensitization and cross-sensitization to methamphetamine (MA)

BACKGROUND: Like other psychostimulant drugs, acute exposure to benzylpiperazine (BZP) increases dopaminergic neurotransmission, producing hyperactivity and stereotypy. The consequences of repeated BZP exposure have not however been investigated. The effects of acute and repeated BZP and methamphetamine (MA) exposure on locomotor activity and stereotypy were measured in order to determine whether there was sensitization and cross-sensitization between these two psychostimulant drugs. METHODS: The effects of acute treatment with MA (0.0, 0.5, 1.0 and 2.0 mg/kg, intraperitoneal (IP)) or BZP (0.0, 5.0, 10.0, 20.0 and 40.0 mg/kg, IP) on locomotor activity and stereotypy were determined. Effects of repeated exposure were determined in other groups that received five daily injections of 2.0 mg/kg MA, 20.0 mg/kg BZP or vehicle. Following a 2-day withdrawal period, rats from each treatment group received either a low dose MA (0.5 mg/kg) or BZP (10.0 mg/kg). RESULTS: MA and BZP produced dose-dependent hyperactivity and stereotypy. Repeated MA and BZP resulted in a potentiated locomotor but not stereotypy response. Following the withdrawal period, MA pretreated rats exhibited a sensitized locomotor and stereotypy response to the low dose MA and a conditioned response to saline. BZP pretreated rats also demonstrated a sensitized locomotor response to the low dose of BZP and MA. CONCLUSIONS: The present findings indicate that repeated exposure to BZP results in sensitization and cross-sensitization to MA.