Investigation of the effects of lamotrigine and clozapine in improving reversal-learning impairments induced by acute phencyclidine and d-amphetamine in the rat

• Published in: Psychopharmacologia Vol. 179; no. 2; pp. 336 - 348
• Main Authors: IDRIS, N. F, REPETO, P, NEILL, J. C, LARGE, C. H
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.05.2005; Springer Nature B.V
• Subjects: Animals; Antimanic Agents - pharmacology; Antipsychotic Agents - pharmacology; Biological and medical sciences; Central Nervous System Stimulants - antagonists & inhibitors; Central Nervous System Stimulants - toxicity; Clozapine - pharmacology; Conditioning, Operant - drug effects; Dextroamphetamine - antagonists & inhibitors; Dextroamphetamine - toxicity; Dose-Response Relationship, Drug; Drug toxicity and drugs side effects treatment; Female; Hallucinogens - antagonists & inhibitors; Hallucinogens - toxicity; Haloperidol - pharmacology; Learning Disorders - chemically induced; Learning Disorders - prevention & control; Medical sciences; Pharmacology. Drug treatments; Phencyclidine - antagonists & inhibitors; Phencyclidine - toxicity; Rats; Reversal Learning - drug effects; Toxicity: nervous system and muscle; Triazines - pharmacology; Amphetamine derivatives; D-Amphetamine; Cognitive disorder; Rat; Neuroleptic; Psychotropic; Toxicity; Schizophrenia; Glutamate receptor; Anticonvulsant; Haloperidol; Cognitive deficit; Psychosis; Phencyclidine; Anesthetic; Reversal learning; Piperidine derivatives; Hallucinogen; Amfetamine; CNS stimulant; Dopamine antagonist; Acute; Rodentia; Butyrophenone derivatives; Neuroprotective agent; Clozapine; Vertebrata; Mammalia; D2 Dopamine receptor; Animal; Triazine derivatives; NMDA receptor; Lamotrigine
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-004-2058-5

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. 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. Female hooded-Lister rats were food deprived and trained to respond for food in a reversal-learning paradigm. 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). 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.