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Publication
Dorsal BNST a2A-Adrenergic Receptors Produce HCN-Dependent Excitatory Actions
That Initiate Anxiogenic Behaviors.
Authors Harris NA, Isaac AT, Günther A, Merkel K, Melchior J, Xu M, Eguakun E, Perez R,
Nabit BP, Flavin S, Gilsbach R, Shonesy B, Hein L, Abel T, Baumann A, Matthews
R, Centanni SW, Winder DG
Submitted By Submitted Externally on 11/5/2018
Status Published
Journal The Journal of neuroscience : the official journal of the Society for Neuroscience
Year 2018
Date Published 10/1/2018
Volume : Pages 38 : 8922 - 8942
PubMed Reference 30150361
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. a2A-adrenergic
receptors (a2A-ARs) in extended amygdala structures play key roles in dampening
stress responses. Contrary to early thinking, a2A-ARs are expressed at
non-noradrenergic sites in the brain. These non-noradrenergic a2A-ARs play
important roles in stress responses, but their cellular mechanisms of action are
unclear. In humans, the a2A-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 a2A-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.SIGNIFICANCE STATEMENT Stress affects the development of
neuropsychiatric disorders including anxiety and addiction. Guanfacine is an
a2A-adrenergic receptor (a2A-AR) agonist with actions in the bed nucleus of the
stria terminalis (BNST) that produces antidepressant actions and uncouples
stress from reward-related behaviors. Here, we show that guanfacine increases
dorsal BNST neuronal activity through actions at postsynaptic a2A-ARs via a
mechanism that involves hyperpolarization-activated cyclic nucleotide gated
cation channels. This action is mimicked by activation of the designer receptor
hM4Di expressed in the BNST, which also induces anxiety-like behaviors.
Together, these data suggest that postsynaptic a2A-ARs in BNST have excitatory
actions on BNST neurons and that these actions can be phenocopied by the
so-called "inhibitory" DREADDs, suggesting that care must be taken regarding
interpretation of data obtained with these tools.




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