Dorsal BNST α2A -Adrenergic Receptors Produce HCN-Dependent Excitatory Actions That Initiate Anxiogenic Behaviors

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Nicholas A HarrisDanny G Winder

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. α2A-adrenergic receptors (α2A-ARs) in extended amygdala structures play key roles in dampening stress responses. Contrary to early thinking, α2A-ARs are expressed at non-noradrenergic sites in the brain. These non-noradrenergic α2A-ARs play important roles in stress responses, but their cellular mechanisms of action are unclear. In humans, the α2A-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 α2A-ARs 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 clozapine-N-oxide activation of the Gi-coupled DREADD hM4Di...Continue Reading

Citations

Feb 20, 2020·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Rafael E PerezDanny G Winder
Mar 11, 2020·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Daniel Lustberg, David Weinshenker
Feb 17, 2019·Journal of Neural Transmission·Artur PałaszRyszard Wiaderkiewicz
Aug 9, 2020·Brain, Behavior, and Immunity·Amanda MorganSachin Patel
Jun 13, 2021·Nature Communications·Joseph R LuchsingerSamuel W Centanni

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