Chronic haloperidol-amphetamine interactions and mesolimbic dopamine.

As low-dose amphetamine stimulation of locomotor activity in the rat depends upon a mesolimbic dopaminergic substrate, neuroleptic antagonism of this behavior has been suggested as a model for studying antipsychotic activity. Animals in the present study received 21 days of chronic treatment with 1.0 mg/kg amphetamine, 0.1 mg/kg haloperidol or a combination of these two drugs. On day 21, mesolimbic (but not striatal) dopamine (DA) concentrations were positively related to locomotor activity in an open field. DA metabolites in this region were inversely correlated with the behavior. The combined drug group showed saline-like levels of both behavioral activity and mesolimbic DA. Metabolic indices in this group suggested that increased DA availability partially competed with the neuroleptic receptor blockade in mesolimbic regions. In contrast to tolerance previously observed with cataleptic doses of neuroleptics, 21 days of 0.1 mg/kg haloperidol did not induce behavioral or biochemical tolerance. This finding is consistent with the lack of tolerance development to antipsychotic effects and suggests that animal models incorporating chronic low-dose neuroleptic regimens may be useful for the study of chronic treatment issues.