Differences between haloperidol- and pimozide-induced withdrawal syndrome: a role for Ca2+ channels.

We investigated the behavioral and biochemical events appearing in rats after withdrawal for 24 h or 8-12 days from two classical neuroleptics, haloperidol and pimozide. The neuroleptics were given for 14 days alone or shortly after injection of the Ca2+ channel blocker nifedipine. We have found that withdrawal effects after haloperidol and pimozide were different. After haloperidol treatment we observed an increase in cortical Ca2+ channel and limbic dopamine D1 receptor density and an increase in spontaneous motor activity and apomorphine-induced hyperactivity and stereotypy. In contrast no biochemical changes were observed during pimozide withdrawal, and locomotor activity and responses to apomorphine were depressed. Co-administration of nifedipine with haloperidol prevented the observed biochemical and behavioral symptoms of withdrawal. Nifedipine administration did not change the depressant effects of pimozide. Our results suggest that the voltage-dependent Ca2+ channel is involved in the observed withdrawal syndrome of neuroleptics, and that the absence of this syndrome after pimozide may be related to its considerable Ca2+ channel-blocking properties.