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


OBJECTIVE
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.
Idris
N F
NF
The School of Pharmacy, The University of Bradford, Bradford, West Yorkshire, BD7 1DP, UK.
Repeto
P
P
Neill
J C
JC
Large
C H
CH
D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D003024:Clozapine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D003913:Dextroamphetamine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006213:Hallucinogens / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D006220:Haloperidol / Q000494:pharmacology; D000077213:Lamotrigine; D007859:Learning Disabilities / Q000139:chemically induced* / Q000517:prevention & control*; D010622:Phencyclidine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051381:Rats; D012193:Reversal Learning / Q000187:drug effects*; D014227:Triazines / Q000494:pharmacology*
D018692:Antimanic Agents; D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D006213:Hallucinogens; D014227:Triazines; D010622:Phencyclidine; D003024:Clozapine; D006220:Haloperidol; D003913:Dextroamphetamine; D000077213:Lamotrigine