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- Title
Dorsal BNST α <sub>2A</sub>-Adrenergic Receptors Produce HCN-Dependent Excitatory Actions That Initiate Anxiogenic Behaviors.
- Authors
Harris, Nicholas A.; Isaac, Austin T.; Gunther, Anne; Merkel, Kevin; Melchior, James; Xu, Michelle; Eguakun, Eghosa; Perez, Rafael; Nabit,, Brett P.; Flavin, Stephanie; Gilsbach, Ralf; Shonesy, Brian; Hein, Lutz; Abel, Ted; Baumann, Arnd; Matthews, Robert; Centanni, Samuel W.; Winder, Danny G.
- Abstract
Stress is a precipitating agent in neuropsychiatric disease and initiates relapse to drug-seeking behavior in addicted patients. Targeting the stress system in protracted abstinence from drugs of abuse with anxiolytics may be an effective treatment modality for substance use disorders. α 2A-adrenergic receptors (α 2A-ARs) in extended amygdala structures play key roles in dampening stress responses. Contrary to early thinking, α 2A-ARs are expressed at non-noradrenergic sites in the brain. These non-noradrenergic α 2A-ARs play important roles in stress responses, but their cellular mechanisms of action are unclear. In humans, the α 2A-AR agonist guanfacine reduces overall craving and uncouples craving from stress, yet minimally affects relapse, potentially due to competing actions in the brain. Here, we show that heteroceptor cx2 A - A R s postsynaptically enhance dorsal bed nucleus of the stria terminalis (dBNST) neuronal activity in mice of both sexes. This effect is mediated by hyperpolarization-activated cyclic nucleotide-gated cation channels because inhibition of these channels is necessary and sufficient for excitatory actions. Finally, this excitatory action is mimicked by dozapine-N-oxide activation of the Gi< coupled DREADD hM4Di in dBNST neurons and its activation elicits anxiety-like behavior in the elevated plus maze. Together, these data provide a framework for elucidating cell-specific actions of GPCR signaling and provide a potential mechanism whereby competing anxiogenic and anxiolytic actions of guanfacine may affect its clinical utility in the treatment of addiction.
- Subjects
DRUG abstinence; SUBSTANCE abuse; DRUG abuse; ANXIETY; TREATMENT of addictions; DRUG-seeking behavior; ADDICTIONS
- Publication
Journal of Neuroscience, 2018, Vol 38, Issue 42, p8922
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.0963-18.2018