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


The α2a-adrenergic receptor (α2a-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 α2a-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 α2a-AR heteroreceptor signaling might decrease the beneficial efficacy of guanfacine. We aimed to determine the role of α2a-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. We used a genetic deletion strategy and the cocaine CPP procedure to first define the contributions of α2a-AR heteroreceptors to stress-induced reinstatement. Next, we mimicked BNST Gi-coupled α2a-AR heteroreceptor signaling using a Gi-coupled designer receptor exclusively activated by designer drug (Gi-DREADD) approach. Finally, we evaluated the effects of low-dose guanfacine on BNST cFOS immunoreactivity and stress-induced reinstatement. We show that α2a-AR heteroreceptor deletion disrupts stress-induced reinstatement and that BNST Gi-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 α2a-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.

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Fig. 1: Full or heteroreceptor α2A-AR KO does not disrupt the acquisition or extinction of cocaine CPP.
Fig. 2: Full or heteroreceptor α2A-AR KO disrupts stress-induced reinstatement of cocaine CPP.
Fig. 3: Full or heteroreceptor deletion of α2A-ARs does not induce stress-dependent biases in side occupancy in cocaine-naïve mice.
Fig. 4: Activation of Gi signaling within the BNST reinstates cocaine CPP.
Fig. 5: A dose of guanfacine that does not increase BNST cFOS blocks stress-induced reinstatement of cocaine CPP.


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We thank Drs. John D. Allison and Bob Matthews, for technical assistance.

Author information




R.E.P. conceived the study, designed and performed experiments, and co-wrote the paper. A.B. analyzed data, validated viral deposits, and contributed to writing. B.P.N. piloted behavioral studies. N.A.H. performed surgery, assisted in experimental design, and analysis. O.M.F. performed surgery. S.P., R.G., and L.H. provided materials and resources. D.G.W. conceived the study, designed experiments, and co-wrote the paper.

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Correspondence to Danny G. Winder.

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Perez, R.E., Basu, A., Nabit, B.P. et al. α2A-adrenergic heteroreceptors are required for stress-induced reinstatement of cocaine conditioned place preference. Neuropsychopharmacol. 45, 1473–1481 (2020).

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