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Title page for ETD etd-08302018-191009


Type of Document Dissertation
Author Harris, Nicholas Andrew
Author's Email Address nicholas.a.harris@vanderbilt.edu
URN etd-08302018-191009
Title Characterization of novel excitatory actions of alpha2A-adrenergic receptors in the bed nucleus of the stria terminalis
Degree PhD
Department Molecular Physiology and Biophysics
Advisory Committee
Advisor Name Title
Sachin Patel, MD PhD Committee Chair
Colleen Niswender, PhD Committee Member
Danny Winder, PhD Committee Member
Roger Colbran, PhD Committee Member
Terunaga Nakagawa, MD PhD Committee Member
Keywords
  • alpha2a adrenergic receptor
  • HCN channels
  • guanfacine
  • bed nucleus of the stria terminalis
  • stress-induced reinstatement
  • anxiety
Date of Defense 2018-08-07
Availability restricted
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.
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