D₂-family receptors in schizophrenia: Distribution and implications for treatment

The distribution of the D₂ family of dopamine receptors in human brain argues for an interest in the D₃ and D₄ receptors in schizophrenia. The D₄ receptor is not only the prime target for clozapine but also highly and differentially localized to the neocortex, thalamus, and hippocampus. These are central nervous system areas of direct interest in schizophrenia. The initial therapeutic directions in this area will target receptor antagonists. Moreover, because the D₃ receptor may mediate functional actions opposite those mediated by the D₂ receptor, its pharmacology in schizophrenia may also be important. The use of selective antagonists to test these concepts is important. Partial agonists at these different receptors should eventually be targeted and tested in schizophrenia since these drugs could have antagonist (antipsychotic) effects without any antagonist side effects. We report early results of tests with (-)-3PPP, which suggest that there is some antipsychotic action, even though tolerance and uneven clinical actions are apparent. These areas are only beginning to be explored in schizophrenia and require much more research to fully exploit. Drugs that are available to the clinician that act selectively at the D₂-, D₃-, and D₄-receptor sites will be essential in this work.