dc.creator | Harris, Nicholas Andrew | |
dc.date.accessioned | 2020-08-22T20:54:32Z | |
dc.date.available | 2020-08-31 | |
dc.date.issued | 2018-08-31 | |
dc.identifier.uri | https://etd.library.vanderbilt.edu/etd-08302018-191009 | |
dc.identifier.uri | http://hdl.handle.net/1803/14048 | |
dc.description.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. 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 BNST (dBNST) neuronal activity in mice of both sexes. This effect is mediated by hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels, as 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, this data provides a framework for elucidating cell-specific actions of GPCR signaling and provides a potential mechanism whereby competing anxiogenic and anxiolytic actions of guanfacine may affect its clinical utility in the treatment of addiction. | |
dc.format.mimetype | application/pdf | |
dc.subject | alpha2a adrenergic receptor | |
dc.subject | HCN channels | |
dc.subject | guanfacine | |
dc.subject | bed nucleus of the stria terminalis | |
dc.subject | stress-induced reinstatement | |
dc.subject | anxiety | |
dc.title | Characterization of novel excitatory actions of alpha2A-adrenergic receptors in the bed nucleus of the stria terminalis | |
dc.type | dissertation | |
dc.contributor.committeeMember | Colleen Niswender, PhD | |
dc.contributor.committeeMember | Roger Colbran, PhD | |
dc.contributor.committeeMember | Terunaga Nakagawa, MD PhD | |
dc.contributor.committeeMember | Danny Winder, PhD | |
dc.type.material | text | |
thesis.degree.name | PHD | |
thesis.degree.level | dissertation | |
thesis.degree.discipline | Molecular Physiology and Biophysics | |
thesis.degree.grantor | Vanderbilt University | |
local.embargo.terms | 2020-08-31 | |
local.embargo.lift | 2020-08-31 | |
dc.contributor.committeeChair | Sachin Patel, MD PhD | |