Activator of G protein signaling 3: a gatekeeper of cocaine sensitization and drug seeking.
Chronic cocaine administration reduces G protein signaling efficacy. Here, we report that the expression of AGS3, which binds to GialphaGDP and inhibits GDP dissociation, was upregulated in the prefrontal cortex (PFC) during late withdrawal from repeated cocaine administration. Increased AGS3 was mimicked in the PFC of drug-naive rats by microinjecting a peptide containing the Gialpha binding domain (GPR) of AGS3 fused to the cell permeability domain of HIV-Tat. Infusion of Tat-GPR mimicked the phenotype of chronic cocaine-treated rats by manifesting sensitized locomotor behavior and drug seeking and by increasing glutamate transmission in nucleus accumbens. By preventing cocaine withdrawal-induced AGS3 expression with antisense oligonucleotides, signaling through Gialpha was normalized, and both cocaine-induced relapse to drug seeking and locomotor sensitization were prevented. When antisense oligonucleotide infusion was discontinued, drug seeking and sensitization were restored. It is proposed that AGS3 gates the expression of cocaine-induced plasticity by regulating G protein signaling in the PFC.
Bowers
M Scott
MS
Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, SC 29425, USA.
McFarland
Krista
K
Lake
Russell W
RW
Peterson
Yuri K
YK
Lapish
Christopher C
CC
Gregory
Mary Lee
ML
Lanier
Stephen M
SM
Kalivas
Peter W
PW
D000818:Animals; D016739:Behavior, Addictive / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D051381:Rats; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000378:metabolism
D002352:Carrier Proteins; C498913:Gpsm1 protein, rat; D016376:Oligonucleotides, Antisense; D003042:Cocaine