Clozapine prolongs hypotonic immobility in rats with bilateral 6-hydroxydopamine lesions of the striatum

Clozapine does not induce classical catalepsy. One explanation is that endogenous dopamine (DA) readily displaces clozapine from postsynaptic striatal DA receptors. If the latter were true, then depletion of striatal DA should permit clozapine to induce classical catalepsy. Rats received bilateral sham or 6-hydroxydopamine (6-OHDA) lesions of the striatum. Catalepsy using the bar test was assessed on days 21, 28 and 35 after i.p. vehicle, haloperidol (0.75 mg/kg) or clozapine (20 mg/kg). Brains were harvested on day 36 and striatal DA was assayed. A 97% depletion of striatal DA was associated with a significant increase in the duration of immobility after haloperidol or clozapine administration. Both in sham as well as in 6-OHDA lesioned animals, however, the duration of immobility was greater after haloperidol than after clozapine. Furthermore, clozapine-treated animals were hypotonic and did not show the classic rigidity of haloperidol catalepsy. While clozapine's low propensity to induce immobility in animals and extrapyramidal symptoms in man may depend in part on endogenous striatal DA, other mechanisms must also be involved.