The involvement of dopamine D1 and D2 receptors in the effects of the classical neuroleptic haloperidol and the atypical neuroleptic clozapine.

There is increasing evidence that classical neuroleptics (neuroleptics that induce so called extrapyramidal side effects) and atypical neuroleptic drugs (neuroleptics that do not induce these side effects) have different mechanisms of action. It has been suggested that atypical neuroleptics may work at least partially through the dopamine D1 receptor whereas classical neuroleptics are generally considered to work via the dopamine D2 receptor. In order to test this hypothesis we evaluated the role of D1 and D2 receptors in the effects of haloperidol and clozapine in the paw test. This test has been shown to be a good animal model for both the therapeutic efficacy of classical and atypical neuroleptics as well as for the extrapyramidal side effect potential of classical neuroleptics. The present results show that the effects of haloperidol in the paw test are antagonised by a dopamine D2 agonist but not by a D1 agonist, whereas the effects of clozapine are reversed by a D1 agonist but not by a D2 agonist. These data suggest that haloperidol produces its therapeutic and extrapyramidal side effects via blockade of dopamine D2 receptors, whereas clozapine produces its therapeutic effects via blockade of dopamine D1 receptors.