Differential effects of clozapine and pimozide on fixed-ratio responding during repeated dosing

Previous research has shown that the differential development of tolerance to the disruption of operant responding produced by repeated dosing with pimozide (PMZ) or clozapine (CLZ) can distinguish these two drugs. In the present study, the effects of PMZ (1 mg/kg) and CLZ (10 mg/kg) on response rate and response duration in rats lever pressing for food reward under a fixed-ratio 30 (FR-30) operant schedule were examined. PMZ suppressed response rates across all 10 days of drug dosing; CLZ produced an initial response rate decrease, with partial recovery (50%) occurring within the 10 day period. Similarly, PMZ produced an increase in response duration that persisted into the postdrug vehicle-injection period, while CLZ did not significantly change response duration. The prolonged suppression of FR responding produced by PMZ is similar to the lack of tolerance to this drug in other types of operant schedules. In contrast, CLZ's effects on response rate are schedule dependent. These results suggest that changes in response duration with repeated dosing may more reliably differentiate typical and atypical neuroleptics than do changes in response rate under FR schedules.