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 a and beta gamma subunits. G alpha(i) inhibits cAMP production, but beta gamma regulates several molecular pathways, including protein kinase A (PKA). We show in NAc/striatal neurons that opiates paradoxically activate PKA signaling by means of beta gamma climers. Activation requires G alpha(i3) and an activator of G protein signaling 3 (AGS3). AGS3 competes with beta gamma for binding to G alpha(i3)-GDP and enhances the action of unbound beta gamma. AGS3 and G alpha(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, G alpha(i3)/beta gamma/AGS3 appears to mediate mu opiate receptor activation of PKA signaling as well as heroin-seeking behavior.