Alcoholism and relapse in abstinent alcoholics are major health problems world-wide and current research is underway to identify potential pharmaceutical treatments for these disorders. However, heavy alcohol use and binge alcohol drinking by non-dependent individuals have received far less attention. A 'binge'is defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) as a pattern of drinking that produces blood alcohol concentrations (BACs) greater than 0.08% (80 mg/dL) within a short period of time. Frequent binge drinking has been linked to numerous negative consequences, including an increased likelihood of developing mood disorders, high blood pressure and heart disease, and type-2 diabetes. Of greatest concern, regular binge drinking significantly increases ones risk of developing alcohol dependence. Thus, it is of paramount importance to identify neurochemical pathways in the brain that modulate binge drinking as such knowledge will provide insight into novel pharmaceutical treatments that will protect against this dangerous behavior. Neuropeptide Y (NPY) is expressed in brain regions implicated in neurobiological responses to alcohol and NPY protects against excessive alcohol intake associated with dependence. Thus, we recently studied the role of NPY receptor signaling in binge-like drinking. Central administration of NPY significantly blunted binge-like alcohol drinking (in mice that achieved BACs of >100 mg/dL in the absence of NPY) but did not decrease drinking in mice with moderate levels of consumption (associated with BACs of <25 mg/dL). The effects of NPY on binge-like drinking are modulated by the Y1R and Y2R (but not Y5R) receptors. Importantly, our preliminary observations also revealed that binge-like drinking is associated with a significant reduction of NPY immunoreactivity in the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST). Thus, the guiding hypothesis for the present proposal is that NPY signaling modulates binge- like alcohol intake. The proposed Aims will use powerful and innovative electrophysiological, histological (immunoreactivity), genetic (real-time PCR), and anatomical (site-directed manipulation of NPY signaling) techniques to determine if: A) binge-like alcohol drinking will be associated with altered NPY expression and receptor signaling that become rigid with repeated binge-like episodes (Aims 1 &3), B) NPY receptor signaling within the extended amygdala modulates binge-like alcohol drinking (Aim 2), and C) the mechanism that triggers blunted NPY signaling and motivates binge-like drinking involves epigenetic elements, specifically alterations of histone acetylation (Aim 2). Expected results from the current project would identify Y1R agonists, Y2R antagonists, and compounds that increase histone acetylation as attractive targets for treating binge drinking. Pharmaceutical interventions useful for curbing and/or preventing binge drinking will not only help individuals avoid many of the dangerous health consequences associated with regular binge drinking, but may protect vulnerable individuals from progressing to the point of alcohol dependence.

Public Health Relevance

While current research is underway to identify potential pharmaceutical treatments for preventing excessive alcohol intake associated with dependence, far less attention is given to potential treatments to curb excessive binge drinking in non-dependent individuals, despite numerous negative health consequences associated with this dangerous behavior. Research has established that compounds aimed at neuropeptide Y (NPY) receptors are protective against dependence-induced alcohol drinking, and our preliminary findings suggest that compounds targeting NPY receptors are also protective against excessive binge-like drinking in mice. Expected results will verify that compounds aimed at NPY receptors are useful for curbing and/or preventing binge drinking, and will not only help individuals avoid many of the health consequences associated with regular binge drinking, but may protect vulnerable individuals from progressing to the point of alcohol dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA013573-12
Application #
8668817
Study Section
Special Emphasis Panel (ZRG1-IFCN-A (03))
Program Officer
Grakalic, Ivana
Project Start
2001-07-01
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
12
Fiscal Year
2014
Total Cost
$282,015
Indirect Cost
$93,721
Name
University of North Carolina Chapel Hill
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Sprow, Gretchen M; Rinker, Jennifer A; Thiele, Todd E (2014) Histone acetylation in the nucleus accumbens shell modulates ethanol-induced locomotor activity in DBA/2J mice. Alcohol Clin Exp Res 38:2377-86
Wilcox, Mark V; Cuzon Carlson, Verginia C; Sherazee, Nyssa et al. (2014) Repeated binge-like ethanol drinking alters ethanol drinking patterns and depresses striatal GABAergic transmission. Neuropsychopharmacology 39:579-94
Thiele, Todd E; Crabbe, John C; Boehm 2nd, Stephen L (2014) "Drinking in the Dark" (DID): a simple mouse model of binge-like alcohol intake. Curr Protoc Neurosci 68:9.49.1-9.49.12
Olney, J J; Sprow, G M; Navarro, M et al. (2014) The protective effects of the melanocortin receptor (MCR) agonist, melanotan-II (MTII), against binge-like ethanol drinking are facilitated by deletion of the MC3 receptor in mice. Neuropeptides 48:47-51
Thiele, Todd E; Navarro, Montserrat (2014) "Drinking in the dark" (DID) procedures: a model of binge-like ethanol drinking in non-dependent mice. Alcohol 48:235-41
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
Lerma-Cabrera, Jose M; Carvajal, Francisca; Chotro, Gabriela et al. (2013) MC4-R signaling within the nucleus accumbens shell, but not the lateral hypothalamus, modulates ethanol palatability in rats. Behav Brain Res 239:51-4
Navarro, Montserrat; Cubero, Inmaculada; Thiele, Todd E (2013) Decreased immunoreactivity of the polypeptide precursor pro-opiomelanocortin (POMC) and the prohormone convertase pc1/3 after chronic ethanol exposure in Sprague-Dawley rats. Alcohol Clin Exp Res 37:399-406
Lerma-Cabrera, Jose Manuel; Carvajal, Francisca; Alcaraz-Iborra, Manuel et al. (2013) Adolescent binge-like ethanol exposure reduces basal *-MSH expression in the hypothalamus and the amygdala of adult rats. Pharmacol Biochem Behav 110:66-74
Lowery-Gionta, Emily G; Navarro, Montserrat; Li, Chia et al. (2012) Corticotropin releasing factor signaling in the central amygdala is recruited during binge-like ethanol consumption in C57BL/6J mice. J Neurosci 32:3405-13

Showing the most recent 10 out of 45 publications