Review the role of dopamine D4 receptors in schizophrenia and antipsychotic action.

For the past 20 years the most enduring explanation for schizophrenia has been the dopamine hypothesis, which proposes that the dopaminergic system is overactive in this widespread disease. Classically, the D2 receptor formed the core of the dopamine hypothesis since there was considerable evidence for elevations of D2 receptor levels in the brains of schizophrenic patients, and because these receptors served as the primary target in mediating antipsychotic effects of most neuroleptics. However, the dopamine D4 receptor has recently received particular attention in this context. This is because the atypical antipsychotic, clozapine, which is effective in treating refractory schizophrenics without the side-effect profile of typical neuroleptics, displays a 10-fold higher affinity for D4 compared to D2 or D3 receptors. Furthermore, the concentration in plasma water of clinical doses ofclozapine correlates well with its in vitro binding affinity for D4, but not D2 or D3 receptors, suggesting that D4 is a potential target in mediating clozapine's antipsychotic effects. As well, marked elevations in the level of a D4-like site (not identical to the D4 receptor) has been seen in the striatum of postmortem schizophrenic brains, but not in control brains. Finally, the most interesting feature of the D4 receptor is perhaps the array of polymorphisms associated with it, creating structural diversity in this receptor that supercedes all other known catecholamine receptors. The existence of these D4 polymorphisms raises the possibility that structural variations of this receptor may be associated with an increased susceptibility to schizophrenia, or observed variations in individual response to clozapine treatment. However, several studies aimed at investigating these hypotheses could not establish a direct role of D4 in schizophrenia. Furthermore, no association was evident between the polymorphic forms of D4 and susceptibility to schizophrenia, or variable clozapine response. Nevertheless, investigations surrounding this receptor has been far from futile. The observations which support the idea that D4 might serve as a target for clozapine have significantly modified and extended our understanding of mechanisms underlying atypical antipsychotic treatment of schizophrenia, as well as the dopamine hypothesis for schizophrenia. Further characterization of this receptor may prove to be crucial in designing highly effective antipsychotic drugs with minimal contraindications.