Nucleus accumbens AGS3 expression drives ethanol seeking through G betagamma.
Approximately 90% of alcoholics relapse within 4 years, in part because of an enhanced motivation to seek alcohol (EtOH). A novel G protein modulator (Gpsm1/AGS3) was up-regulated in the rat nucleus accumbens core (NAcore) but not in other limbic nuclei during abstinence from operant EtOH self-administration. Furthermore, NAcore AGS3 knockdown reduced EtOH seeking to pre-abstinence levels in a novel rat model of compulsive, human EtOH seeking. AGS3 can both inhibit G protein G i alpha-mediated signaling and stimulate G betagamma-mediated signaling. Accordingly, sequestration of G betagamma, but not G i alpha knockdown, significantly reduced EtOH seeking to pre-abstinence levels. Thus, AGS3 and G betagamma are hypothesized to gate the uncontrolled motivation to seek EtOH during abstinence. AGS3 up-regulation during abstinence may be a key determinant of the transition from social consumption to compulsion-like seeking during relapse.
Bowers
M Scott
MS
Ernest Gallo Clinic and Research Center, Department of Neurology, University of California at San Francisco, Emeryville, CA 94608, USA.
Hopf
F Woodward
FW
Chou
Jonathan K
JK
Guillory
Anitra M
AM
Chang
Shao-Ju
SJ
Janak
Patricia H
PH
Bonci
Antonello
A
Diamond
Ivan
I
D000428:Alcohol Drinking / Q000235:genetics*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology*; D000431:Ethanol; D020555:GTP-Binding Protein Regulators / Q000235:genetics; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism*; D008297:Male; D009714:Nucleus Accumbens / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D015854:Up-Regulation
D002352:Carrier Proteins; D020555:GTP-Binding Protein Regulators; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; C498913:Gpsm1 protein, rat; D000431:Ethanol; D019206:GTP-Binding Protein alpha Subunits, Gi-Go