Dopamine D3 receptor as a therapeutic target for antipsychotic and antiparkinsonian drugs

The cloning of the gene for the D-3 receptor and subsequent identification of its distribution in brain and pharmacology allowed for serious consideration of the possibility that it might be a target for drugs used to treat schizophrenia and Parkinson's disease (PD). That is because it is highly expressed in limbic regions of the brain, exhibits low expression in motor divisions, and has pharmacologic similarity to the D-2 receptor. Thus, antipsychotics that were presumed to block D-2 receptors also had high affinity for the D-3 receptor. Dopamine agonists used to treat the clinical symptoms of PD also have high affinity for the D-3 receptor, and two D-3 receptor-preferring agonists were found to be effective for treatment of PD. Many compounds achieving high potency and selectivity are now available, but few have reached clinical testing. Recent findings with respect to the anatomy of this receptor in human brain, altered expression in schizophrenia and PD, and biological models to study its function support the proposal that it is a target for development of drugs to alleviate symptoms in neuropsychiatric and neurologic disorders. Because of distinct aspects of regulation of the D-3 receptor, it represents a unique target for therapeutic intervention in schizophrenia without high potential for unintended side effects such as tardive dyskinesia. It may also be that D-3 receptor agonists can provide neuroprotective effects in PD and can modify clinical symptoms that D-2 receptor-preferring agonists cannot provide. (C) 2001 Elsevier Science Inc. All rights reserved.