Clozapine and prazosin slow the rhythm of head movements during focused stereotypy induced by d-amphetamine in rats

Abstract

Clozapine is an efficacious, symptom-ameliorating, atypical antipsychotic drug with few extrapyramidal side effects. Clozapine has been reported either not to affect or to increase d-amphetamine-induced stereotypy, a behavior that is blocked by typical antipsychotic drugs. This work used a high-resolution measurement system to reassess clozapine's effects on d-amphetamine-induced focused stereotypy (FS) in rats. A force-plate actometer permitted the quantitation of the rhythm and vigor of movements during FS. Eight rats received a sensitizing series of doses of 5.0 mg/kg d-amphetamine sulfate, and this dosing regimen induced head movements with a rhythm near 10 Hz. Thirty minutes after d-amphetamine treatment, rats received acute clozapine (2.5-10.0 mg/kg), followed by eight, daily clozapine injections (5.0 mg/kg) given with d-amphetamine on days 2, 5, and 8. Effects of acute doses of the alpha1-noradrenergic antagonist prazosin (0.5-2.0 mg/kg) on the d-amphetamine response were also examined. Clozapine dose-dependently slowed the near 10-Hz rhythm and reduced the vigor of the d-amphetamine-induced FS. Clozapine significantly lengthened the duration of the FS phase, but the rhythm remained slowed. No evidence for tolerance to clozapine's rhythm-slowing effects was seen in the subchronic phase. Prazosin dose-dependently reduced the near 10-Hz rhythm induced by d-amphetamine, but prazosin did not lengthen the FS phase. The results show that clozapine diminished the rhythm and vigor of d-amphetamine-induced stereotyped head movements but, at the same time, lengthened the duration of the expression of the stereotypy. alpha1 antagonism is a likely contributor to the rhythm-modulating effects of clozapine.