Behavioral effects of clozapine and dopamine receptor subtypes

The atypical neuroleptic clozapine (CLZ) is an extremely effective antipsychotic that produces relatively few motoric side effects. However, CLZ displays limited antagonism at the dopamine (DA) D2 receptor, the receptor commonly thought to mediate the antipsychotic activity of neuroleptics. The mechanism of action behind the efficacy of CLZ remains to be determined. Miller, Wickens and Beninger [Progr. Neurobiol., 34, 143-184 (1990)] propose a "D1 hypothesis of antipsychotic action" that may explain the antipsychotic effects of CLZ. This hypothesis is built on the interactions between D2, cholinergic and D1 mechanisms in the striatum. These authors assert that although typical neuroleptics block D2 receptors, it is through an indirect action on D1 receptors that their antipsychotic action is manifest. The extra-pyramidal side effects produced by typical neuroleptics are hypothesized to be due to an indirect action on cholinergic receptors. It is argued that the anticholinergic properties of CLZ negate the D2 (motor side effects) action of CLZ, allowing CLZ to diminish psychotic symptoms through a direct action on D1 receptors. Thus, CLZ may function as a D1 receptor antagonist in behavioral paradigms. The current paper reviews and compares the behavioral profile of CLZ to those produced by D2- and D1-selective antagonists with specific reference to unconditioned and conditioned behaviors in order to more fully evaluate the "D1 hypothesis of CLZ action". Although the actions of CLZ remain unique, they do share some striking similarities with D1 receptor antagonists especially in tests of unconditioned behavior, possibly implicating the D1 receptor in the action of this antipsychotic drug.