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J Neurosci. 2018 Oct 17;38(42):8922-8942. doi: 10.1523/JNEUROSCI.0963-18.2018. Epub 2018 Aug 27.

Dorsal BNST α2A-Adrenergic Receptors Produce HCN-Dependent Excitatory Actions That Initiate Anxiogenic Behaviors.

Author information

Vanderbilt Center for Addiction Research.
Department of Molecular Physiology and Biophysics.
Department of Psychiatry and Behavioral Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
Laboratory for Synaptic Molecules of Memory Persistence, RIKEN Center for Brain Science, Japan.
School for Science and Math at Vanderbilt.
Department of Pharmacology.
Vanderbilt Brain Institute.
Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg 79104, Germany.
BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg 79104, Germany, and.
Iowa Neuroscience Institute, Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242.
Department of Cellular Biophysics, Forschungszentrum Jülich, Germany.
Vanderbilt Center for Addiction Research,
Vanderbilt J.F. Kennedy Center for Research on Human Development.


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.SIGNIFICANCE STATEMENT Stress affects the development of neuropsychiatric disorders including anxiety and addiction. Guanfacine is an α2A-adrenergic receptor (α2A-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 α2A-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 α2A-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.


HCN channels; alpha2a-adrenergic receptor; anxiety; bed nucleus of the stria terminalis; guanfacine; norepinephrine

[Available on 2019-04-17]

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