Dopamine D2 and D4 receptor ligands:: relation to antipsychotic action

Since the discovery that the antipsychotic action of phenothiazines was mediated by dopamine D-2 receptors, the dopamine system has been scrutinized for schizophrenia related abnormalities. The focus has been to create neuroleptics with improved antipsychotic profiles and reduced side effects. With the identification of multiple dopamine receptor subtypes, the hypotheses regarding the role of dopamine in schizophrenia and antipsychotic action of neuroleptics have been refined. Even after the molecular identification of newer dopamine D-2-like receptor subtypes (D-3 and D-4), the dopamine D-2 receptor is still considered the predominant site for antipsychotic action. However, there has been much debate concerning the modulatory role of other dopamine receptor sites in the mechanism of action of antipsychotic drugs. Specifically, the dopamine D-4 receptor has received much attention in this regard, since the atypical antipsychotic agent, clozapine, preferentially blocks this receptor subtype as compared with dopamine D-2 and D-3 receptors. In this review we will highlight some of the observations and arguments regarding the involvement of the dopamine D-2 and D-4 receptor sites in the therapeutic efficacy of antipsychotic medication. (C) 1998 Elsevier Science B.V. All rights reserved.