Activator of G protein signaling 3: a gatekeeper of cocaine sensitization and drug seeking.
Journal: 2004/June - Neuron
ISSN: 0896-6273
PUBMED: 15091342
Abstract:
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.
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Neuron 42(2): 269-281

Activator of G-protein Signaling 3: A Gatekeeper of Cocaine Sensitization and Drug-seeking

Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, SC 29425
Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112

Summary

Chronic cocaine administration reduces G-protein signaling efficacy. Here we report that the expression of AGS3, which selectively 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 naïve 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 rats pretreated with chronic cocaine by manifesting sensitized locomotor behavior and drug-seeking, as well as increased 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. Based on these findings it is proposed that AGS3 gates the expression of cocaine-induced behavioral plasticity by regulating G-protein signaling in the PFC.

Keywords: cocaine, addiction, G protein, AGS3, prefrontal cortex, reinstatement, microdialysis, sensitization, Gi
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