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The α 2a -adrenergic receptor (α 2a -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 α 2a -AR autoreceptors, it also activates excitatory G i -coupled heteroreceptors in the bed nucleus of the stria terminalis (BNST), a key brain region in driving stress-induced relapse. Thus, BNST α 2a -AR heteroreceptor signaling might decrease the beneficial efficacy of guanfacine. We aimed to determine the role of α 2a -AR heteroreceptors and BNST G i -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. We used a genetic deletion strategy and the cocaine CPP procedure to first define the contributions of α 2a -AR heteroreceptors to stress-induced reinstatement. Next, we mimicked BNST G i -coupled α 2a -AR heteroreceptor signaling using a G i -coupled designer receptor exclusively activated by designer drug (G i -DREADD) approach. Finally, we evaluated the effects of low-dose guanfacine on BNST cFOS immunoreactivity and stress-induced reinstatement. We show that α 2a -AR heteroreceptor deletion disrupts stress-induced reinstatement and that BNST G i -DREADD activation is sufficient to induce reinstatement. Importantly, we found that low-dose guanfacine does not increase BNST activity, but prevents stress-induced reinstatement. Our findings demonstrate a role for α 2a -AR heteroreceptors and BNST G i -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.

α2A-adrenergic heteroreceptors are required for stress-induced reinstatement of cocaine conditioned place preference