RGS9 modulates dopamine signaling in the basal ganglia

Zia Rahman; Johannes Schwarz; Stephen J. Gold; Venetia Zachariou; Marc N. Wein; Kwang Ho Choi; Abraham Kovoor; Ching Kang Chen; Ralph J. DiLeone; Sigrid C. Schwarz; Dana E. Selley; Laura J. Sim-Selley; Michel Barrot; Robert R. Luedtke; David Self; Rachael L. Neve; Henry A. Lester; Melvin I. Simon; Eric J. Nestler

doi:10.1016/S0896-6273(03)00321-0

RGS9 modulates dopamine signaling in the basal ganglia

Zia Rahman, Johannes Schwarz, Stephen J. Gold, Venetia Zachariou, Marc N. Wein, Kwang Ho Choi, Abraham Kovoor, Ching Kang Chen, Ralph J. DiLeone, Sigrid C. Schwarz, Dana E. Selley, Laura J. Sim-Selley, Michel Barrot, Robert R. Luedtke, David Self, Rachael L. Neve, Henry A. Lester, Melvin I. Simon, Eric J. Nestler

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231 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	941-952
Number of pages	12
Journal	Neuron
Volume	38
Issue number	6
DOIs	https://doi.org/10.1016/S0896-6273(03)00321-0
State	Published - Jun 19 2003

ASJC Scopus subject areas

General Neuroscience

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Rahman, Z., Schwarz, J., Gold, S. J., Zachariou, V., Wein, M. N., Choi, K. H., Kovoor, A., Chen, C. K., DiLeone, R. J., Schwarz, S. C., Selley, D. E., Sim-Selley, L. J., Barrot, M., Luedtke, R. R., Self, D., Neve, R. L., Lester, H. A., Simon, M. I., & Nestler, E. J. (2003). RGS9 modulates dopamine signaling in the basal ganglia. Neuron, 38(6), 941-952. https://doi.org/10.1016/S0896-6273(03)00321-0

@article{ffaf6908c0b94f9a92a213b94206c2cc,

title = "RGS9 modulates dopamine signaling in the basal ganglia",

abstract = "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.",

author = "Zia Rahman and Johannes Schwarz and Gold, {Stephen J.} and Venetia Zachariou and Wein, {Marc N.} and Choi, {Kwang Ho} and Abraham Kovoor and Chen, {Ching Kang} and DiLeone, {Ralph J.} and Schwarz, {Sigrid C.} and Selley, {Dana E.} and Sim-Selley, {Laura J.} and Michel Barrot and Luedtke, {Robert R.} and David Self and Neve, {Rachael L.} and Lester, {Henry A.} and Simon, {Melvin I.} and Nestler, {Eric J.}",

note = "Funding Information: 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.",

year = "2003",

month = jun,

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doi = "10.1016/S0896-6273(03)00321-0",

language = "English (US)",

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pages = "941--952",

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T1 - RGS9 modulates dopamine signaling in the basal ganglia

AU - Rahman, Zia

AU - Schwarz, Johannes

AU - Gold, Stephen J.

AU - Zachariou, Venetia

AU - Wein, Marc N.

AU - Choi, Kwang Ho

AU - Kovoor, Abraham

AU - Chen, Ching Kang

AU - DiLeone, Ralph J.

AU - Schwarz, Sigrid C.

AU - Selley, Dana E.

AU - Sim-Selley, Laura J.

AU - Barrot, Michel

AU - Luedtke, Robert R.

AU - Self, David

AU - Neve, Rachael L.

AU - Lester, Henry A.

AU - Simon, Melvin I.

AU - Nestler, Eric J.

N1 - Funding Information: 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.

PY - 2003/6/19

Y1 - 2003/6/19

N2 - 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.

AB - 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.

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U2 - 10.1016/S0896-6273(03)00321-0

DO - 10.1016/S0896-6273(03)00321-0

M3 - Article

C2 - 12818179

AN - SCOPUS:0037860972

SN - 0896-6273

VL - 38

SP - 941

EP - 952

JO - Neuron

JF - Neuron

IS - 6

ER -

RGS9 modulates dopamine signaling in the basal ganglia

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