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 ethanol concentrations (BECs) greater than 0.08% (80 mg/dL) within a short period of time. Of great concern, regular binge drinking significantly increases ones risk of developing ethanol 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. We have found that binge-like ethanol drinking increases corticotropin releasing factor (CRF) immunoreactivity (IR) in the central amygdala (CeA) and that a type-1 receptor (CRF1R) antagonist, when injected into the CeA, protects against excessive binge-like drinking in C57BL/6J mice. On the other hand, CRF1R antagonists fail to alter moderate non-binge-like ethanol intake. These observations parallel evidence that CRF1R antagonists blunt dependence-like drinking without altering ethanol intake in non-dependent animals. The guiding hypothesis for this grant is that acute binge-like ethanol drinking transiently engages CRF signaling in the CeA, and at sites that are innervated by CRF pathways arising from the CeA, and drives continued excessive ethanol intake. We further hypothesize that increased CRF signaling fails to """"""""normalize"""""""" with repeated binge-like drinking episodes, ultimately contributing to persistent increases in alcohol drinking. The proposed Aims will use powerful and innovative electrophysiological, histological, genetic, and behavioral techniques to determine if: A) A history of repeated binge-like drinking episodes will be associated with changes in CRF and CRF receptor levels and function (Aim 1), B) CRF1R antagonist and a CRF2R agonist will protect against binge-like ethanol drinking when injected into the CeA and regions that receive CRF innervation from the CeA (Aim 2), and C) inhibition of CRF-producing neurons in the CeA and/or bed nucleus of the stria terminalis (BNST) with designer receptors that are exclusively activated by designer drugs (DREADDs) will protect against binge-like ethanol drinking, and DREADD-induced activation of CRF-producing neurons in these regions will increase binge-like drinking (Aim 3). These highly innovative projects will provide a shift in pre-clinical alcoholism research by providing insight into the role for CRF1R and CRF2R signaling in excessive binge-like ethanol drinking and the transition to a dependence-like state, and establish new technologies for studying the neurocircuitry that modulates excessive ethanol intake.

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, including the development of alcohol dependence. Research has established that compounds aimed at corticotropin releasing factor (CRF) receptors are protective against dependence-induced alcohol drinking, and our findings show that that compounds targeting CRF receptors are also protective against excessive binge-like drinking in mice. Expected results will show that compounds aimed at CRF 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.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-Q (03))
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Grandison, Lindsey
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University of North Carolina Chapel Hill
Schools of Arts and Sciences
Chapel Hill
United States
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Olney, Jeffrey J; Marshall, S Alex; Thiele, Todd E (2018) Assessment of depression-like behavior and anhedonia after repeated cycles of binge-like ethanol drinking in male C57BL/6J mice. Pharmacol Biochem Behav 168:1-7
Companion, Michel A; Thiele, Todd E (2018) Assessment of ventral tegmental area-projecting GABAergic neurons from the bed nucleus of the stria terminalis in modulating binge-like ethanol intake. Eur J Neurosci 48:3335-3343
Burnham, Nathan W; Thiele, Todd E (2017) Voluntary Binge-like Ethanol Consumption Site-specifically Increases c-Fos Immunoexpression in Male C57BL6/J Mice. Neuroscience 367:159-168
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