Dopamine receptor downregulation: an alternative strategy for schizophrenia treatment.
Schizophrenia is a common and devastating illness. The cause of schizophrenia is still unknown and the simplest formulation of the "Dopamine hypothesis" posits that schizophrenia results from dopaminergic hyperactivity. Under the hypothesis of dopaminergic hyperactivity in schizophrenia, antipsychotics blocking the dopamine D2 receptor (DRD2) and other approaches to reduce dopamine (DA) transmission have been used to treat schizophrenia. I propose that dopamine receptor (DR) downregulation could be an alternative strategy to compromise dopaminergic overactivity implicated in the pathogenesis of schizophrenia. Agonist-induced receptor downregulation includes receptor proteolysis, modulation of receptor gene transcription and affecting of RNA stability. These processes cause a decrease of existing receptors and reduction of receptor synthesis. This hypothesis could explain the antipsychotic mechanisms of DA agonists or partial agonists, like aripiprazole. It is suggested that the development of agents that increase DR downregulation could be an alternative strategy for schizophrenia treatment.
Tsai
Shih-Jen
SJ
Department of Psychiatry, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, No. 201 Shih-Pai Road, Sec. 2, Taipei 11217, Taiwan, ROC. sjtsai@vghtpe.gov.tw
D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D000068180:Aripiprazole; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018492:Dopamine Antagonists / Q000627:therapeutic use*; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D008959:Models, Neurological; D010879:Piperazines / Q000627:therapeutic use*; D015363:Quinolones / Q000627:therapeutic use*; D011954:Receptors, Dopamine / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism*; D016896:Treatment Outcome
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D010879:Piperazines; D015363:Quinolones; D011954:Receptors, Dopamine; D000068180:Aripiprazole