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 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.
Rahman
Zia
Z
Department of Psychiatry and Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Schwarz
Johannes
J
Gold
Stephen J
SJ
Zachariou
Venetia
V
Wein
Marc N
MN
Choi
Kwang Ho
KH
Kovoor
Abraham
A
Chen
Ching Kang
CK
DiLeone
Ralph J
RJ
Schwarz
Sigrid C
SC
Selley
Dana E
DE
Sim-Selley
Laura J
LJ
Barrot
Michel
M
Luedtke
Robert R
RR
Self
David
D
Neve
Rachael L
RL
Lester
Henry A
HA
Simon
Melvin I
MI
Nestler
Eric J
EJ
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D004553:Electric Conductivity; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D015870:Gene Expression; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000737:chemistry; D009865:Oocytes / Q000378:metabolism; D015221:Potassium Channels / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying; D020710:RGS Proteins / Q000032:analysis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000502:physiology; D015398:Signal Transduction; D014162:Transfection; D014981:Xenopus
D000697:Central Nervous System Stimulants; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D020710:RGS Proteins; D017448:Receptors, Dopamine D2; C116925:regulator of g-protein signaling 9; D003042:Cocaine; D004298:Dopamine