The application proposes a career development plan for Dr. Thomas Kash, a post-doctoral fellow committed to a research career in ethanol addiction aimed towards understand its neurophysiological basis. The initial, mentored phase of the proposal will be conducted at Vanderbilt University in the laboratory of Dr. Danny Winder. The project focuses on the role of dopamine signaling in the extended amygdala in both acute and chronic aspects of alcohol abuse. The extended amygdala, including the bed nucleus of the stria terminalis (BNST) and central nucleus of the amygdala (CeA) receives substantial dopaminergic innervation, and studies suggest that dopamine signaling in these regions is important in stress and addiction-related behaviors Interestingly, a major portion of the dopaminergic innervation of this region originates from the AlODc group of dopamine neurons in the ventral lateral periaqueductal gray (vlPAG), a region strongly implicated in emotional behavior. The present multldisciplinary application uses electrophysiological, anatomical and molecular techniques to determine the mechanisms of dopamine signaling in the BNST and to define the role that AlOdc dopaminergic neurons play in alcohol abuse. The mentored phase of this award will focus on an in-depth examination of the mechanism of dopamine modulation in the BNST, using genetic and pharmacological approaches to test the hypothesis that acute ethanol alters neuronal function of the BNST through activation of dopamine receptors (Aim 1). The focus of the studies vA ] then shift to focus on the role of the AlOdc dopaminergic neurons of the vlPAG in alcohol abuse. The basic characteristics and the abihty of ethanol to modulate function of these neurons will be determined using newly available 'reporter'mice (Aim 2), The impact of chronic ethanol exposure on the electrophysiological parameters and biochemical markers of activation in the AlOdc dopaminergic neurons, as well as dopamine modulation of function in the BNST will be assessed in Aim 3.

Public Health Relevance

The project will provide critical insights in to the role of dopamine in the acute actions of alcohol and define the physiologic relevance of an uncharacterized population of dopaminergic neurons in alcohol abuse and dependence

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Transition Award (R00)
Project #
4R00AA017668-02
Application #
7893285
Study Section
Special Emphasis Panel (NSS)
Program Officer
Cui, Changhai
Project Start
2008-08-01
Project End
2012-06-30
Budget Start
2009-09-15
Budget End
2010-06-30
Support Year
2
Fiscal Year
2009
Total Cost
$249,000
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Peasant, Courtney; Sullivan, Tami P; Weiss, Nicole H et al. (2017) Beyond the syndemic: condom negotiation and use among women experiencing partner violence. AIDS Care 29:516-523
Crowley, Nicole A; Bloodgood, Daniel W; Hardaway, J Andrew et al. (2016) Dynorphin Controls the Gain of an Amygdalar Anxiety Circuit. Cell Rep 14:2774-83
Vardy, Eyal; Robinson, J Elliott; Li, Chia et al. (2015) A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior. Neuron 86:936-946
Williams, Megan A; Li, Chia; Kash, Thomas L et al. (2014) Excitatory drive onto dopaminergic neurons in the rostral linear nucleus is enhanced by norepinephrine in an ?1 adrenergic receptor-dependent manner. Neuropharmacology 86:116-24
Li, Chia; McCall, Nora M; Lopez, Alberto J et al. (2013) Alcohol effects on synaptic transmission in periaqueductal gray dopamine neurons. Alcohol 47:279-87
Cui, Changhai; Noronha, Antonio; Morikawa, Hitoshi et al. (2013) New insights on neurobiological mechanisms underlying alcohol addiction. Neuropharmacology 67:223-32
Cox, Benjamin R; Olney, Jeffrey J; Lowery-Gionta, Emily G et al. (2013) Repeated cycles of binge-like ethanol (EtOH)-drinking in male C57BL/6J mice augments subsequent voluntary EtOH intake but not other dependence-like phenotypes. Alcohol Clin Exp Res 37:1688-95
Li, Chia; Pleil, Kristen E; Stamatakis, Alice M et al. (2012) Presynaptic inhibition of gamma-aminobutyric acid release in the bed nucleus of the stria terminalis by kappa opioid receptor signaling. Biol Psychiatry 71:725-32
Roberto, Marisa; Kash, Thomas L; Mulholland, Patrick J et al. (2012) Introduction to Young Investigator Award Symposium: Symposium XII: Young Investigator Award. Alcohol 46:301-2
Holmes, Andrew; Fitzgerald, Paul J; MacPherson, Kathryn P et al. (2012) Chronic alcohol remodels prefrontal neurons and disrupts NMDAR-mediated fear extinction encoding. Nat Neurosci 15:1359-61

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