RGS9 modulates dopamine signaling in the basal ganglia |
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Authors: | Rahman Zia Schwarz Johannes Gold Stephen J Zachariou Venetia Wein Marc N Choi Kwang Ho Kovoor Abraham Chen Ching Kang DiLeone Ralph J Schwarz Sigrid C Selley Dana E Sim-Selley Laura J Barrot Michel Luedtke Robert R Self David Neve Rachael L Lester Henry A Simon Melvin I Nestler Eric J |
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Institution: | Department of Psychiatry and Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. |
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Abstract: | Regulators of G protein signaling (RGS) modulate heterotrimeric G proteins in part by serving as GTPase-activating proteins for Galpha 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. |
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