Clozapine fails to prevent the development of haloperidol-induced behavioral hypersensitivity in a cotreatment paradigm.

We have previously established that chronic cotreatments involving antimuscarinic agents and haloperidol attenuate the development of behavioral hypersensitivity without affecting dopamine receptor proliferation. The antipsychotic agent clozapine also has significant antimuscarinic activity and was coadministered with haloperidol in rats for 2 months to determine if it would similarly attenuate the development of hypersensitivity. Clozapine or chlorpromazine cotreatment, unlike thioridazine cotreatment, did not attenuate the development of haloperidol-induced behavioral hypersensitivity. Clozapine or thioridazine cotreatment also failed to prevent the development of haloperidol-induced D2 receptor proliferation, whereas chlorpromazine cotreatment enhanced D2 receptor proliferation relative to haloperidol-treated animals. Alterations in dopamine biochemistry in the striatum or nucleus accumbens could not explain this dissociation between behavioral hypersensitivity and dopamine receptor proliferation. It is therefore hypothesized that dopamine receptor proliferation is permissive for behavioral hypersensitivity and that factors in addition to alterations in dopamine function contribute to the expression of dopamine hypersensitivity states.