Role of Alpha2a-Adrenergic Heteroreceptors in Stress-Induced Reinstatement of Cocaine Associated Behaviors: Implications for the Pharmacological Treatment of Stress-Driven Relapse of Drug Use

Abstract

The A2a-adrenergic receptor (A2a-AR) agonist guanfacine has been investigated as a potential treatment for substance use disorders. While decreasing stress-induced reinstatement of cocaine seeking in animal models and stress-induced craving in human studies, guanfacine has not been reported to decrease relapse rates. Although guanfacine engages A2a-AR autoreceptors, it also activates excitatory Gi-coupled heteroreceptors in the bed nucleus of the stria terminalis (BNST), a key brain region in driving stress-induced relapse. Thus, BNST A2a-AR heteroreceptor signaling might decrease the beneficial efficacy of guanfacine. The role of A2a-AR heteroreceptors and BNST Gi-GPCR signaling in stress-induced reinstatement of cocaine conditioned place preference (CPP) and the effects of low dose guanfacine on BNST activity and stress-induced reinstatement were examined. A genetic deletion strategy and the cocaine CPP procedure were used to first define the contributions of A2a-AR heteroreceptors to stress-induced reinstatement. Next, BNST Gi-coupled A2a-AR heteroreceptor signaling was mimicked using a Gi-coupled designer receptor exclusively activated by designer drug (Gi-DREADD) approach. Finally, the effects of low-dose guanfacine on BNST cFOS immunoreactivity and stress-induced reinstatement we investigated. We show that A2a-AR heteroreceptor deletion disrupts stress-induced reinstatement and that BNST Gi-DREADD activation is sufficient to induce reinstatement. Importantly, low-dose guanfacine does not increase BNST activity, but prevents stress-induced reinstatement. These findings demonstrate a role for A2a-AR heteroreceptors and BNST Gi-GPCR signaling in stress-induced reinstatement of cocaine CPP and provide insight into the impact of dose on the efficacy of guanfacine as a treatment for stress-induced relapse of cocaine use.