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 -