Activator of G protein signaling 3 regulates opiate activation of protein kinase A signaling and relapse of heroin-seeking behavior.

The nucleus accumbens (NAc) is central to heroin addiction. Activation of opiate receptors in the NAc dissociates G(i/o) into alpha and betagamma subunits. Galpha(i) inhibits cAMP production, but betagamma regulates several molecular pathways, including protein kinase A (PKA). We show in NAc/striatal neurons that opiates paradoxically activate PKA signaling by means of betagamma dimers. Activation requires Galpha(i3) and an activator of G protein signaling 3 (AGS3). AGS3 competes with betagamma for binding to Galpha(i3)-GDP and enhances the action of unbound betagamma. AGS3 and Galpha(i3) knockdown prevents opiate activation of PKA signaling. In rats self-administering heroin, AGS3 antisense in the NAc core, but not shell, eliminates reinstatement of heroin-seeking behavior, a model of human relapse. Thus, Galpha(i3)/betagamma/AGS3 appears to mediate mu opiate receptor activation of PKA signaling as well as heroin-seeking behavior.