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