Supersensitivity to dopaminergic agonists induced by haloperidol.

Haloperidol caused a significant reduction in the spontaneous locomotor activity of mice when added to their diet for 11 days. Upon removal of the drug from their diet these mice exhibited withdrawal hyperactivity for several days that was characterized by an increase in activity over control or pre-halopericol values. Similar results were obtained when mice were fed a diet containing pimozide. Withdrawal hyperactivity was not detected after 1 or 3 days of haloperidol containing diet, but was maximal after 6 days of this diet. Dose-response curves of apomorphine-stimulated motor activity and rearing behavior were shifted to the left when determined in mice during the period of withdrawal hyperactivity. Dopaminergic agonists (apomorphine, piribedil, L-DOPA and d-amphetamine) induced gnawing at lower doses in mice removed from a chronic haloperidol-containing diet for 2 days than in mice maintained on a control diet. These results support the hypothesis that prolonged blockade of central dopaminergic receptors by neuroleptics causes subsequent behavioral effects that may be due to the development of enhanced receptor sensitivity.