The importance of dopamine D4 receptors in the action and development of antipsychotic agents.

The dopamine D4 receptor, recently identified by molecular biological techniques, is expressed in areas of the brain implicated in the pathophysiology of schizophrenia. Although it has a lower affinity than the D2 receptor for most antipsychotic drugs, the D4 receptor has a higher affinity for clozapine, which may explain the unique efficacy of clozapine in the treatment of schizophrenia. However, there is no association between genetic alterations of the D4 gene and either the development of schizophrenia or response to clozapine administration, nor is the absence of the receptor related to major neuropsychiatric deficits. The report of an increase in D4 receptor density in the striatum in schizophrenia has not been consistently confirmed. Thus, it appears that there is little to support the development of D4 antagonists as potential antipsychotic agents.