Investigation of the effects of lamotrigine and clozapine in improving reversal-learning impairments induced by acute phencyclidine and D-amphetamine in the rat.
Idris, Nagi F. Repeto, P. Neill, Joanna C. Large, C.H.
Idris, Nagi F.
Repeto, P.
Neill, Joanna C.
Large, C.H.
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2005
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Abstract
Rationale Phencyclidine (PCP), a glutamate/N-methyl-d-aspartate (NMDA) receptor antagonist, has been shown to induce a range of symptoms similar to those of patients with schizophrenia, while d-amphetamine induces predominantly positive symptoms. Previous studies in our laboratory have shown that PCP can selectively impair the performance of an operant reversal-learning task in the rat. Furthermore, we found that the novel antipsychotic ziprasidone, but not the classical antipsychotic haloperidol, could prevent the PCP-induced deficit.
Objectives The aim of the present study was to validate the model further using the atypical antipsychotic clozapine and then to investigate the effects of lamotrigine, a broad-spectrum anticonvulsant that is known to reduce glutamate release in vitro and is able to prevent ketamine-induced psychotic symptoms in healthy human volunteers. A further aim was to compare effects of PCP and d-amphetamine in the test and investigate the effects of the typical antipsychotic haloperidol against the latter.
Methods Female hooded-Lister rats were food deprived and trained to respond for food in a reversal-learning paradigm.
Results PCP at 1.5 mg/kg and 2.0 mg/kg and d-amphetamine at 0.5 mg/kg significantly and selectively impaired performance in the reversal phase of the task. The cognitive deficit induced by 1.5 mg/kg PCP was attenuated by prior administration of lamotrigine (20 mg/kg and 30 mg/kg) or clozapine (5 mg/kg), but not haloperidol (0.05 mg/kg). In direct contrast, haloperidol (0.05 mg/kg), but not lamotrigine (25 mg/kg) or clozapine (5 mg/kg), prevented a similar cognitive impairment produced by d-amphetamine (0.5 mg/kg).
Conclusions Our findings provide further data to support the use of PCP-induced disruption of reversal learning in rodents to investigate novel antipsychotic drugs. The results also provide evidence for different mechanisms of PCP and d-amphetamine-induced disruption of performance in the test, and their different sensitivities to typical and atypical antipsychotic drugs.
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Idris, N. F., Repeto, P., Neill, J. C. and Large, C. H. (2005). Investigation of the effects of lamotrigine and clozapine in improving reversal-learning impairments induced by acute phencyclidine and D-amphetamine in the rat. Psychopharmacology, Vol. 179, No. 2, pp.336-348.
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