Chronic administration of clozapine alleviates reversal-learning impairment in isolation-reared rats

Isolation rearing has been used for inducing schizophrenia-like symptoms in rats. Human schizophrenics have deficits in prefrontal-dysfunction-related cognitive/behavioral flexibility. Rats with lesions of the medial prefrontal cortex perform poorly in reversal learning. It is uncertain whether isolation rearing, however, causes reversal-learning impairment in adult rats. Using the rotating T maze, this study examined the effect of chronic administration of clozapine on visual discrimination learning and reversal learning in isolation-reared and socially reared adult rats. The results show that isolation-reared rats without clozapine injection performed significantly worse than socially reared rats in reversal learning but not in acquisition learning. Chronic injection of clozapine (5 or 10 mg/kg) in isolation-reared rats significantly improved reversal learning but had no effects on acquisition learning. Further data analyses show that in both the inhibition phase and the new-strategy-acquisition phase of reversal learning, isolation-reared rats needed significantly more correct-response trials to reach the criterion than socially reared rats, and clozapine significantly reduced the isolation-induced impairment of reversal learning only in the new-strategy-acquisition phase. In socially reared rats, clozapine had a dose-related interfering effect on reversal learning but not acquisition learning. This study supports the use of isolation rearing as a model for investigating the neurodevelopmental hypothesis of schizophrenia.