DOPAMINE D-4 RECEPTORS - POTENTIAL THERAPEUTIC IMPLICATIONS IN THE TREATMENT OF SCHIZOPHRENIA

In contrast to more traditional antipsychotic drugs such as haloperido l, atypical antipsychotics such as clozapine are characterised by low levels of extrapyramidal side effects (EPS) and improved clinical effi cacy. This may result from increased binding to dopamine D-4 and serot onin 5-HT2A and 5-HT2C receptors concomitant with decreased dopamine D -2 receptor blockade, particularly of D-2 sites in the striatum where EPS are thought to originate. Although there is no genetic evidence fo r a direct role of variation in the Dq receptor gene in schizophrenia, a role for variation in the 5-HT2A receptor gene is supported by gene tic and biochemical studies. This does not preclude the D-4 receptor a s a major therapeutic target for antipsychotic drugs, especially since it is expressed predominantly in the cortex and limbic system, where the antipsychotic effects of drugs such as clozapine are thought to be mediated. As novel serotonin-dopamine receptor antagonists with defin ed pharmacological profiles become available, the careful analysis of the relationship between receptor binding profiles and efficacy will d etermine the most important receptor targets for improved antipsychoti c action without the generation of EPS. Furthermore, the role of D-4 r eceptors as therapeutic targets will soon be determined by the use of selective ligands about to be introduced into clinical trials.