TY  - JOUR
AU  - Harris, Nicholas A.
AU  - Isaac, Austin T.
AU  - Günther, Anne
AU  - Merkel, Kevin
AU  - Melchior, James
AU  - Xu, Michelle
AU  - Eguakun, Eghosa
AU  - Perez, Rafael
AU  - Nabit, Brett P.
AU  - Flavin, Stephanie
AU  - Gilsbach, Ralf
AU  - Shonesy, Brian
AU  - Hein, Lutz
AU  - Abel, Ted
AU  - Baumann, Arnd
AU  - Matthews, Robert
AU  - Centanni, Samuel W.
AU  - Winder, Danny G.
TI  - Dorsal BNST α 2A -Adrenergic Receptors Produce HCN-Dependent Excitatory Actions That Initiate Anxiogenic Behaviors
JO  - The journal of neuroscience
VL  - 38
IS  - 42
SN  - 0270-6474
CY  - Washington, DC
PB  - Soc.69657
M1  - FZJ-2018-06356
SP  - 8922-8942
PY  - 2018
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:30150361
UR  - <Go to ISI:>//WOS:000447587500002
DO  - DOI:10.1523/JNEUROSCI.0963-18.2018
UR  - https://juser.fz-juelich.de/record/857102
ER  -