We have been using a combination of genetic and environmental manipulations to induce high ethanol intake in mice, defined as alcohol intake leading to a blood ethanol concentration (BEC) greater than 100 mg%. We determined that exposure to intermittent ethanol vapor and multiple withdrawal episodes (i.e., MW group) produced high ethanol consumption and withdrawal symptoms that were consistent with the development of physical dependence in these animals. This procedure has been termed """"""""Withdrawal-Induced Drinking"""""""" (WID) and is thought to be one behavioral model of the increased alcohol consumption in dependent animals (also termed """"""""dependence-induced"""""""" drinking). Preliminary data indicate that acamprosate (complex glutamatergic modulator), but not naltrexone (opioid receptor antagonist), significantly decreased the expression of WID. Subsequent studies determined that systemic administration of baclofen (GABAB receptor agonist), MPEP (mGluR5 antagonist), and NBI 27914 (CRF1 receptor antagonist) significantly decreased the expression of WID. Finally, intra amygdala administration of the CRF receptor antagonist D-Phe-CRF(12-41) also selectively decreased the high alcohol intake in the MW group without altering ethanol intake in the Control group. The present proposal will continue this line of inquiry with the WID model to determine the key neurotransmitters and neuropeptides that modulate the expression of WID and begin to discern neural sites that are important for the expression of WID. We hypothesize that neuroadaptations in the central nucleus of the amygdala (CeA) and lateral septum are important for the expression of WID.
Aim 1 will pharmacologically manipulate the neurochemical environment of the lateral septum, whereas Aim 2 will manipulate the neurochemical environment of the CeA, to determine the neurotransmitters and neuropeptides that are important for the high alcohol intake and expression of WID in mice. Proposed studies will use a brain site- specific microinjection technique to manipulate the GABAergic, glutamatergic, and CRF peptide environment of the lateral septum and CeA. Microinjection of receptor agonists and antagonists will allow us to determine whether the MW and Control groups are differentially sensitive to these neurochemical manipulations of the CeA and lateral septum, and whether the manipulations are sufficient to modulate the expression of WID. Collectively, the proposed research will examine the neurobiological mechanisms underlying the high alcohol consumption WID phenotype. Not only will this information help in furthering our understanding of the mechanisms underlying dependence-induced drinking, but it also will aid in the development of new strategies for the treatment of alcoholism.

Public Health Relevance

The proposed research will examine the neurobiological mechanisms underlying high alcohol consumption in dependent animals. Studies will use a brain site-specific microinjection technique to determine the key neurotransmitters and neuropeptides that modulate the increased alcohol consumption in dependent animals and begin to discern neural sites that are important for this increased alcohol intake. Not only will this information help in furthering our understanding of the mechanisms underlying dependence-induced drinking, but it also will aid in the development of new strategies for the treatment of alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA016981-04
Application #
8127662
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Egli, Mark
Project Start
2008-09-15
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
4
Fiscal Year
2011
Total Cost
$263,780
Indirect Cost
Name
Oregon Health and Science University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Cozzoli, Debra K; Kaufman, Moriah N; Nipper, Michelle A et al. (2016) Functional regulation of PI3K-associated signaling in the accumbens by binge alcohol drinking in male but not female mice. Neuropharmacology 105:164-174
Cozzoli, Debra K; Courson, Justin; Rostock, Charlotte et al. (2016) Protein Kinase C Epsilon Activity in the Nucleus Accumbens and Central Nucleus of the Amygdala Mediates Binge Alcohol Consumption. Biol Psychiatry 79:443-51
Gomez, Juan L; Cunningham, Christopher L; Finn, Deborah A et al. (2015) Differential effects of ghrelin antagonists on alcohol drinking and reinforcement in mouse and rat models of alcohol dependence. Neuropharmacology 97:182-93
Ramaker, Marcia J; Strong-Kaufman, Moriah N; Ford, Matthew M et al. (2015) Effect of nucleus accumbens shell infusions of ganaxolone or gaboxadol on ethanol consumption in mice. Psychopharmacology (Berl) 232:1415-26
Ramaker, M J; Ford, M M; Phillips, T J et al. (2014) Differences in the reinstatement of ethanol seeking with ganaxolone and gaboxadol. Neuroscience 272:180-7
Cozzoli, Debra K; Tanchuck-Nipper, Michelle A; Kaufman, Moriah N et al. (2014) Environmental stressors influence limited-access ethanol consumption by C57BL/6J mice in a sex-dependent manner. Alcohol 48:741-54
Wyatt, Letisha R; Finn, Deborah A; Khoja, Sheraz et al. (2014) Contribution of P2X4 receptors to ethanol intake in male C57BL/6 mice. Neurochem Res 39:1127-39
Cozzoli, Debra K; Courson, Justin; Wroten, Melissa G et al. (2014) Binge alcohol drinking by mice requires intact group 1 metabotropic glutamate receptor signaling within the central nucleus of the amygdala. Neuropsychopharmacology 39:435-44
Davies, Daryl L; Bortolato, Marco; Finn, Deborah A et al. (2013) Recent advances in the discovery and preclinical testing of novel compounds for the prevention and/or treatment of alcohol use disorders. Alcohol Clin Exp Res 37:8-15
Ramaker, Marcia J; Strong, Moriah N; Ford, Matthew M et al. (2012) Effect of ganaxolone and THIP on operant and limited-access ethanol self-administration. Neuropharmacology 63:555-64

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