Increased sensitivity to dopaminergic agents after chronic neuroleptic treatment

Male CF-1 mice were treated for 14 days with diets containing haloperidol, thioridazine HCl and 4'-fluoro-4[[4-(p-fluorophenyl)-4-methoxycyclohexyl]-amino]-butyrophenone HCl (U35,777A). At various times during and after neuroleptic treatment, spontaneous and d-amphetamine-stimulated motor activity were measured. Two days after cessation of treatment, the mice displayed enhanced spontaneous and d-amphetamine-stimulated motor activity. This effect was no longer apparent 9 days after neuroleptic intake was terminated. With a quantal test based on the climbing activity induced by apomorphine, it was determined that mice were also supersensitive to apomorphine at 2 days but not 9 days after withdrawal from chronic haloperidol. In an attempt to correlate this supersensitivity to a biochemical parameter related to receptor function, dopamine-stimulated adenyl cyclase activity was assayed in striatal homogenates of mice 2 days after haloperidol withdrawal. No alteration in this parameter was observed. Likewise, the ability of apomorphine to elevate striatal cyclic adenosine monophosphate concentrations in vivo was unaltered by withdrawal from chronic haloperidol. Chronic treatment with neuroleptics results in a brief supersensitivity to dopaminergic agents. This effect does not appear to be accompanied by increases in dopamine-stimulated adenyl cyclase activity in the corpus striatum.