Doctor of Philosophy
Joseph H. Porter
This study examined the behavioral and biochemical effects of two neuroleptic drugs. Clozapine (10 mg/kg), an atypical neuroleptic, and pimozide (1 mg/kg), a typical neuroleptic, were administered acutely, chronically (10 days), or in a behavioral tolerance paradigm (9 days of post-session administration followed by 10 days of presession administration) in order to assess the mechanisms of tolerance. Behavioral Effects were measured on a multiple FI 60-second FR-30 operant response schedule; HPLC was used to measure the biochemical effects of clozapine in the blood plasma, frontal cortex and striatum.
Presession administration of clozapine and pimozide both produced initial disruptions of response rate, response duration and reinforcement rate for both the FI and FR schedules, but only clozapine disrupted the pattern of FI responding as measured by IOC. Tolerance develops to the effects of clozapine for FI schedule response rate, response duration and reinforcement rate measures and for the FR response duration measure. Tolerance did not develop to clozapine's disruption of response and reinforcement rates on the FR schedule, nor did tolerance develop to the disruption of the IOC measure. Pimozide groups demonstrated an increasing sensitivity to the effects of the drug after repeated administration for both FI and FR response rate, response duration and reinforcement rate.
Post-session administration of clozapine and pimozide failed to disrupt operant responding and did not affect subsequent presession drug administration. This suggests that both the tolerance to clozapine and the sensitivity to pimozide are mediated by functional mechanisms. Repeated clozapine administration produces a behavioral tolerance whereas repeated pimozide administration produces a "behavioral sensitivity".
Biochemical assays measuring the amounts of clozapine in the blood plasma, frontal cortex and striatum confirm that the tolerance to clozapine is not due to a dispositional mechanism (i.e., changes in drug metabolism). Assays revealed that quantities of clozapine did not differ between the three clozapine groups, nor did clozapine differentially affect the frontal cortex and striatum.
It was concluded that clozapine's response disrupting effects were not due to an anhedonic effect, nor were the disrupting effects due to a motor deficit involving a response termination deficit. Other motor deficits, however, were not discounted. Pimozide appeared to produce a pattern of disruption similar to that produced by extinction, thus suggesting that anhedonic effects were involved.
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