Binge and/or excessive drinking is a problematic component of alcoholism which has been correlated with enhanced alcohol use disorder in adolescents (Hingson et al., 2005;2007;Miller et al. 2007). However, the neural mechanisms that mediate this behavior remain unclear. Here, we utilize a mouse model of binge and/or excessive drinking known as drinking in the dark (DID) to examine corticotropin releasing factor (CRF) signaling in the ventral tegmental area (VTA), a structure involved in the etiology of drug and alcohol abuse. In the DID model, C57BL/6J mice drink approximately 10 g/kg and achieve blood ethanol concentrations of approximately 100 mg/dL or 0.1%, which is equivalent to 4-6 drinks over a 2 hour period in a normal sized human male (Rhodes et al., 2005;2007). CRF is a widely expressed neuropeptide that has been shown to modulate neurobiological responses to ethanol (for review see Koob, 2003). Preliminary data suggest that binge ethanol drinking in mice results in a greater CRF-induced potentiation of NMDA current in VTA dopamine (DA) neurons. However, the CRF receptor subtypes involved in this increased potentiation remain unknown. Therefore, Specific Aim I will examine which CRF receptor subtype mediates this increased NMDA potentiation. For this aim, I will employ patch-clamp electrophysiology.
Specific Aim II will complement the first aim by examining whether intra-VTA administration of selective antagonists (CRFi receptor, CRF2 receptor, CRF-binding protein) reduces the high ethanol consumption associated with DID procedures. 1 hypothesize that binge drinking of ethanol becomes modulated by increased CRFi receptor signaling in the VTA and that blockade of the CRFi receptor in the VTA will reduce high ethanol consumption associated with excessive binge-like drinking. By utilizing both in vitro and in vivo techniques, I feel that I will fully be able to address the questions presented in this proposal. Results from this proposal will identify a possible pharmacological target (CRF signaling in the VTA) that may be useful in targeting specific alcoholic patient populations.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AA018610-01
Application #
7753783
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Cui, Changhai
Project Start
2009-08-16
Project End
2012-08-15
Budget Start
2009-08-16
Budget End
2010-08-15
Support Year
1
Fiscal Year
2009
Total Cost
$47,210
Indirect Cost
Name
Ernest Gallo Clinic and Research Center
Department
Type
DUNS #
173995366
City
Emeryville
State
CA
Country
United States
Zip Code
94608
Stamatakis, Alice M; Sparta, Dennis R; Jennings, Joshua H et al. (2014) Amygdala and bed nucleus of the stria terminalis circuitry: Implications for addiction-related behaviors. Neuropharmacology 76 Pt B:320-8
Sparta, Dennis R; Jennings, Joshua H; Ung, Randall L et al. (2013) Optogenetic strategies to investigate neural circuitry engaged by stress. Behav Brain Res 255:19-25
Sparta, Dennis R; Hopf, Frederic Woodward; Gibb, Stuart L et al. (2013) Binge ethanol-drinking potentiates corticotropin releasing factor R1 receptor activity in the ventral tegmental area. Alcohol Clin Exp Res 37:1680-7
Jennings, Joshua H; Sparta, Dennis R; Stamatakis, Alice M et al. (2013) Distinct extended amygdala circuits for divergent motivational states. Nature 496:224-8
Stuber, Garret D; Sparta, Dennis R; Stamatakis, Alice M et al. (2011) Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking. Nature 475:377-80
Sparta, Dennis R; Stamatakis, Alice M; Phillips, Jana L et al. (2011) Construction of implantable optical fibers for long-term optogenetic manipulation of neural circuits. Nat Protoc 7:12-23