Activator of G protein signaling 3: A gatekeeper of cocaine sensitization and drug seeking

M. Scott Bowers, Krista McFarland, Russell W. Lake, Yuri K. Peterson, Christopher C. Lapish, Mary Lee Gregory, Stephen M. Lanier, Peter W. Kalivas

Research output: Contribution to journalArticle

187 Scopus citations

Abstract

Chronic cocaine administration reduces G protein signaling efficacy. Here, we report that the expression of AGS3, which binds to GiαGDP 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 Giα 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 Giα 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.

Original languageEnglish (US)
Pages (from-to)269-281
Number of pages13
JournalNeuron
Volume42
Issue number2
DOIs
StatePublished - Apr 22 2004

ASJC Scopus subject areas

  • Neuroscience(all)

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    Bowers, M. S., McFarland, K., Lake, R. W., Peterson, Y. K., Lapish, C. C., Gregory, M. L., Lanier, S. M., & Kalivas, P. W. (2004). Activator of G protein signaling 3: A gatekeeper of cocaine sensitization and drug seeking. Neuron, 42(2), 269-281. https://doi.org/10.1016/S0896-6273(04)00159-X