Chronic low-dose haloperidol effects on self-stimulation rate-intensity functions.

Animals responding for biphasic square wave stimulation to the VTA were treated for 26 days with a low dose (0.07 mg/kg) of the neuroleptic haloperidol and tested at 1 h post-injection. Initially the drug induced a pronounced lateral displacement of the baseline rate-intensity function, concomitant with a depression in slope. Over the course of chronic treatment, partial tolerance was observed to the drug-induced increases in threshold concomitant with the onset of a significant suppression in peak response rate. Biochemical tolerance to stimulated dopamine metabolism (as per cent non-drug control) was significant only for mesolimbic (versus neostriatal) regions, in animals receiving haloperidol according to pre- and post-test administration schedules. The observation of sensitization to peak rate reductions parallels previous reports for spontaneous locomotor activity measures and is compatible with depolarization inactivation mechanisms proposed to account for delayed-onset clinical effects. Further, selective biochemical tolerance in mesolimbic regions supports suggestions that mesolimbic dopamine is important as a substrate for subtle low dose neuroleptic effects which may be relevant for studying pharmacotherapeutic treatment issues.