Sulpiride and the role of dopaminergic receptor blockade in the antipsychotic activity of neuroleptics.

It is now generally recognized that dopamine receptors exist in the CNS as different subtypes: D1 receptors, associated with adenylyl cyclase activity, and D2 receptor, uncoupled to a cyclic AMP generating system. In order to understand the role of D1 and D2 receptors in the antipsychotic action of neuroleptics, we have performed subchronic treatment with haloperidol, a drug which acts on D1 receptors, and sulpiride, a selective antagonist to D2 receptors. Long-term treatment with haloperidol does not induce significant supersensitivity of the D2 receptors. In fact under these conditions 3H-(-)-sulpiride binding, which is a marker of D2 receptor function, does not increase in rat striatum, while the long-term administration of sulpiride itself produces supersensitivity of D2 receptors. Moreover, sulpiride does not induce supersensitivity of the D1 receptors, characterized by 3H-spiroperidol binding. These data suggest that both types of dopamine receptors may be involved in the clinical antipsychotic effects of neuroleptics. Unilateral lesion of the nigrostriatal dopaminergic pathway produces an increase of striatal dopaminergic receptors, measured either by 3H-spiroperidol and 3H-(-)-sulpiride binding. These findings suggest that D1 and D2 receptors are present in postsynaptic membranes while it is still not known whether they exist in the same cellular elements.