%0 Journal Article
%A Harris, Nicholas A.
%A Isaac, Austin T.
%A Günther, Anne
%A Merkel, Kevin
%A Melchior, James
%A Xu, Michelle
%A Eguakun, Eghosa
%A Perez, Rafael
%A Nabit, Brett P.
%A Flavin, Stephanie
%A Gilsbach, Ralf
%A Shonesy, Brian
%A Hein, Lutz
%A Abel, Ted
%A Baumann, Arnd
%A Matthews, Robert
%A Centanni, Samuel W.
%A Winder, Danny G.
%T Dorsal BNST α 2A -Adrenergic Receptors Produce HCN-Dependent Excitatory Actions That Initiate Anxiogenic Behaviors
%J The journal of neuroscience
%V 38
%N 42
%@ 0270-6474
%C Washington, DC
%I Soc.69657
%M FZJ-2018-06356
%P 8922-8942
%D 2018
%X 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 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:30150361
%U <Go to ISI:>//WOS:000447587500002
%R 10.1523/JNEUROSCI.0963-18.2018
%U https://juser.fz-juelich.de/record/857102