SIMILARITIES AND DIFFERENCES BETWEEN THE SUBCHRONIC AND WITHDRAWAL EFFECTS OF CLOZAPINE AND OLANZAPINE ON FORELIMB FORCE STEADINESS

The purpose of this study was to compare the subchronic, low-dose effe cts of clozapine with those of olanzapine in a learned behavioral task previously shown to distinguish between clozapine and haloperidol wit h acute and subchronic treatment regimes. Rats were trained to use a s ingle forelimb to press a force-recording operandum and simultaneously to lick water from a dipper that remained available while forelimb fo rce exceeded a modest lower limit. Analysis of the resulting force-tim e recordings provided measures of task engagement (time on task - anal ogous to response rate), lick rhythm, tremor, ballistic (maximum force ) and tonic (hold force) forelimb force measures, as well as the durat ions of the individual responses. In a between-groups dosing design, f ive separate groups of rats received vehicle, clozapine 1.0 or 5.0 mg/ kg, olanzapine 0.5 or 1.0 mg/kg daily for 27 days. A 7-day withdrawal period followed. On days 22 and 26 of antipsychotic drug treatment, al l rats additionally received 0.3 mg/kg trihexyphenidyl or 1.0 mg/kg qu ipazine, respectively. The effects of olanzapine and clozapine were si milar in that both drugs reduced time on task, increased response dura tion, and slowed lick rhythm. The two drugs differed in that clozapine reduced the force and tremor measures but olanzapine did not. Both to lerance and withdrawal effects, as reflected by the tremor measure, we re observed for clozapine but not for olanzapine. Trihexyphenidyl furt her increased the duration of responses already lengthened by clozapin e; in contrast, trihexyphenidyl decreased the duration lengthening eff ect of olanzapine. Taken together, the results indicated that olanzapi ne did not have the antitremor and hypotonic effects displayed by cloz apine, and olanzapine did not induce tolerance and withdrawal phenomen a as clozapine did.