α_2A-adrenergic heteroreceptors are required for stress-induced reinstatement of cocaine conditioned place preference

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.