Fine-tuning of awake prefrontal cortex neurons by clozapine: comparison with haloperidol and N-desmethylclozapine.

Mechanisms underlying clozapine's better clinical efficacy in schizophrenia remain poorly understood. The prefrontal cortex (PFC) has been implicated as a primary site for the therapeutic effects of clozapine; however, evidence for how clozapine influences the activity of PFC neurons in behaviorally relevant contexts is lacking. Ensemble single unit recording in awake rats was used to measure the activity of PFC neurons in response to clozapine, its main metabolite N-desmethylclozapine (DMClz), and the typical antipsychotic drug haloperidol during baseline conditions and after treatment with the N-methyl-D-aspartate antagonist MK801. Behavioral stereotypy was scored during recording. Clozapine and DMClz but not haloperidol had an activity-dependent influence on spontaneous firing rate of PFC cells: they increased the activity of neurons with low baseline firing rates and decreased the activity of neurons with higher firing rates. Clozapine and DMClz but not haloperidol also reversed the effect of MK801 on PFC neuronal firing. This reversal was strongly correlated with blockade of MK801-induced behavioral stereotypy. These findings indicate that clozapine has the capacity to fine-tune spontaneous and disrupted activity of PFC neurons. This effect might contribute, in part, to the therapeutic efficacy of clozapine in schizophrenia.