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Published June 19, 2003 | public
Journal Article

RGS9 Modulates Dopamine Signaling in the Basal Ganglia


Regulators of G protein signaling (RGS) modulate heterotrimeric G proteins in part by serving as GTPase-activating proteins for Gα subunits. We examined a role for RGS9-2, an RGS subtype highly enriched in striatum, in modulating dopamine D2 receptor function. Viral-mediated overexpression of RGS9-2 in rat nucleus accumbens (ventral striatum) reduced locomotor responses to cocaine (an indirect dopamine agonist) and to D2 but not to D1 receptor agonists. Conversely, RGS9 knockout mice showed heightened locomotor and rewarding responses to cocaine and related psychostimulants. In vitro expression of RGS9-2 in Xenopus oocytes accelerated the off-kinetics of D2 receptor-induced GIRK currents, consistent with the in vivo data. Finally, chronic cocaine exposure increased RGS9-2 levels in nucleus accumbens. Together, these data demonstrate a functional interaction between RGS9-2 and D2 receptor signaling and the behavioral actions of psychostimulants and suggest that psychostimulant induction of RGS9-2 represents a compensatory adaptation that diminishes drug responsiveness.

Additional Information

© 2003 Cell Press. Received 18 October 2002, Revised 3 March 2003, Accepted 25 April 2003, Available online 17 April 2004. We wish to thank Dr. William Carlezon, Jr., for helpful discussions; Drs. Vadim Arshavsky, W.F. Simonds, and Andrejs Krummins for antibodies; Cathy Steffen for animal care; and Mike Cassidy, Christina Colby, and Lee Schlesinger for excellent technical support. This work was supported by grants from the National Institute on Drug Abuse (DA08227, DA05274), National Institute of Mental Health (MH66172), National Institute of General Medical Services (GM29836), the Plum Foundation, and by a gift from Ruben Mettler.

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August 19, 2023
October 20, 2023