Journal Article

FZJ-2018-06356

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Dorsal BNST α 2A -Adrenergic Receptors Produce HCN-Dependent Excitatory Actions That Initiate Anxiogenic Behaviors

Harris, N. A. ; Isaac, A. T. ; Günther, A. ; Merkel, K. ; Melchior, J. ; Xu, M. ; Eguakun, E. ; Perez, R. ; Nabit, B. P. ; Flavin, S. ; Gilsbach, R. ; Shonesy, B. ; Hein, L. ; Abel, T. ; Baumann, A.FZJ* ; Matthews, R. ; Centanni, S. W. ; Winder, D. G. (Corresponding author)

2018
Soc.69657 Washington, DC

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Please use a persistent id in citations: http://hdl.handle.net/2128/19970  doi:10.1523/JNEUROSCI.0963-18.2018

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 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.

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Contributing Institute(s):

1. Zelluläre Biophysik (ICS-4)

Research Program(s):

1. 552 - Engineering Cell Function (POF3-552) (POF3-552)

Appears in the scientific report 2018

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Database coverage:
; ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; PubMed Central ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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