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a2A-adrenergic heteroreceptors are required for stress-induced reinstatement of
cocaine conditioned place preference.
Authors Perez RE, Basu A, Nabit BP, Harris NA, Folkes OM, Patel S, Gilsbach R, Hein L,
Winder DG
Submitted By Submitted Externally on 10/12/2020
Status Published
Journal Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Year 2020
Date Published 8/1/2020
Volume : Pages 45 : 1473 - 1481
PubMed Reference 32074627
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. We aimed to determine 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. We used a genetic deletion
strategy and the cocaine CPP procedure to first define the contributions of
a2a-AR heteroreceptors to stress-induced reinstatement. Next, we mimicked BNST
Gi-coupled a2a-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 a2a-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 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.


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