Journal article
Dorsal BNST α2A-Adrenergic Receptors Produce HCN-Dependent Excitatory Actions That Initiate Anxiogenic Behaviors
The Journal of neuroscience, Vol.38(42), pp.8922-8942
10/17/2018
DOI: 10.1523/JNEUROSCI.0963-18.2018
PMCID: PMC6191524
PMID: 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. α
2A
-adrenergic receptors (α
2A
-ARs) in extended amygdala structures play key roles in dampening stress responses. Contrary to early thinking, α
2A
-ARs are expressed at non-noradrenergic sites in the brain. These non-noradrenergic α
2A
-ARs play important roles in stress responses, but their cellular mechanisms of action are unclear. In humans, the α
2A
-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 α
2A
-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 G
i
-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.
Details
- Title: Subtitle
- Dorsal BNST α2A-Adrenergic Receptors Produce HCN-Dependent Excitatory Actions That Initiate Anxiogenic Behaviors
- Creators
- Nicholas A Harris - Vanderbilt Center for Addiction ResearchAustin T Isaac - Vanderbilt Center for Addiction ResearchAnne Günther - Department of Psychiatry and Behavioral Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee 37232Kevin Merkel - Vanderbilt Center for Addiction ResearchJames Melchior - Vanderbilt Center for Addiction ResearchMichelle Xu - Vanderbilt Center for Addiction ResearchEghosa Eguakun - Vanderbilt Center for Addiction ResearchRafael Perez - Vanderbilt Center for Addiction ResearchBrett P Nabit - Vanderbilt Center for Addiction ResearchStephanie Flavin - Vanderbilt Center for Addiction ResearchRalf Gilsbach - Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg 79104, GermanyBrian Shonesy - Vanderbilt Center for Addiction ResearchLutz Hein - Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg 79104, GermanyTed Abel - Iowa Neuroscience Institute, Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Arnd Baumann - Department of Cellular Biophysics, Forschungszentrum Jülich, GermanyRobert Matthews - Vanderbilt Center for Addiction ResearchSamuel W Centanni - Vanderbilt Center for Addiction ResearchDanny G Winder - Vanderbilt Center for Addiction Research
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.38(42), pp.8922-8942
- Publisher
- Society for Neuroscience
- DOI
- 10.1523/JNEUROSCI.0963-18.2018
- PMID
- 30150361
- PMCID
- PMC6191524
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Language
- English
- Date published
- 10/17/2018
- Academic Unit
- Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
- Record Identifier
- 9984070752902771
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