J Neurosci. 2012 Jun 27;32(26):9023-9034.
Anzalone A, Lizardi-Ortiz JE, Ramos M, De Mei C, Hopf FW, Iaccarino C, Halbout B, Jacobsen J, Kinoshita C, Welter M, Caron MG, Bonci A, Sulzer D, Borrelli E.
Department of Microbiology and Molecular Genetics, INSERM U904, University of California Irvine, Irvine, California 92697, Department of Psychiatry, Columbia University, New York, New York 10032, Ernest Gallo Clinic and Research Center, University of California, San Francisco, Emeryville, California 94608, Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland 21224, and Departments of Neurology and Pharmacology, Columbia University, New York, New York 10032.
Dysfunctions of dopaminergic homeostasis leading to either low or high dopamine (DA) levels are causally linked to Parkinson’s disease, schizophrenia, and addiction. Major sites of DA synthesis are the mesencephalic neurons originating in the substantia nigra and ventral tegmental area; these structures send major projections to the dorsal striatum (DSt) and nucleus accumbens (NAcc), respectively. DA finely tunes its own synthesis and release by activating DA D2 receptors (D2R). To date, this critical D2R-dependent function was thought to be solely due to activation of D2Rs on dopaminergic neurons (D2 autoreceptors); instead, using site-specific D2R knock-out mice, we uncover that D2 heteroreceptors located on non-DAergic medium spiny neurons participate in the control of DA levels. This D2 heteroreceptor-mediated mechanism is more efficient in the DSt than in NAcc, indicating that D2R signaling differentially regulates mesolimbic- versus nigrostriatal-mediated functions. This study reveals previously unappreciated control of DA signaling, shedding new light on region-specific regulation of DA-mediated effects