Neuroadaptations in D2‐like autoreceptor function following AMPH self‐administration

Abstract

Exposure to amphetamine (AMPH) self‐administration (0.187 mg/kg/inj, 5 days) results in neuroadaptations in the mesolimbic dopamine system. Dopamine D2‐like autoreceptors are critical modulators of dopaminergic signaling but an understudied topic in drug addiction research. We report a marked subsensitivity of D2 autoreceptors following chronic AMPH. After escalation of AMPH self‐administration in rats, we found that the ability of D2 autoreceptors to inhibit dopamine release was reduced in AMPH rats (IC50 = 200 nM) compared to controls (30 nM), as assessed by voltammetry in the nucleus accumbens core. The reduced function was not due to reduced expression, because AMPH increased D2 short form (presynaptic D2 form) mRNA (46%). To determine the mechanism of D2 subsensitivity, we examined gene expression of the inhibitory subunit of G protein (Gαo) and regulator of G protein signaling 4 (RGS4). Gαo couples to the D2 autoreceptor for signaling, and RGS4 negatively regulates Gαo‐mediated D2 receptor function. We found decreased Gαo mRNA (23%) and increased RGS4 mRNA (27%) in the ventral tegmental area, which likely contribute to the decreased function of D2 autoreceptors following repeated AMPH administration. It is possible that changes in Gαo and RGS4 signaling may be involved in early stages of addiction, increasing dopamine release and contributing to compulsive AMPH‐taking behavior.