Alcohol abuse and dependence constitute a significant health problem for our veterans and the general society alike. A complex interplay among genetic, environmental and experiential factors is known to govern motivation and regulation of alcohol (ethanol) drinking behavior throughout the addiction process. Chronic excessive ethanol consumption can lead to the development of dependence, and repeated experience with associated withdrawal episodes may constitute a powerful motivational force that contributes to the perpetuation of ethanol use/abuse, as well as enhancing vulnerability to relapse. A wide array of neuroadaptive changes in several key motivational brain systems and pathways are known to play a role in behavioral manifestations of dependence and, in particular, contributing to excessive drinking associated with dependence. Identifying new and novel neuroadaptive mechanisms that are provoked in response to chronic ethanol exposure and withdrawal experience, and that underlie transition to excessive uncontrolled drinking is critical for advancing the field and, ultimately, facilitating development of new and more effective treatments for battling the problem of alcohol addiction. Recently, preclinical and clinical evidence has emerged implicating a role for the neurotrophic factor BDNF (Brain-Derived Neurotrophic Factor) in the homeostatic regulation of various ethanol-related behaviors, including ethanol self-administration behavior. However, relatively few studies have examined the role of BDNF in modulating ethanol drinking in the context of dependence. This proposal is aimed at addressing this void in the literature. During the current funding period, we characterized a mouse model of ethanol dependence that we developed, which involves repeated cycles of chronic ethanol exposure and withdrawal and results in robust escalation of voluntary ethanol drinking. Further, we recently collected some novel preliminary data using our dependence model that provides encouraging support for the notion that changes in brain BDNF expression relate to excessive drinking associated with dependence. Accordingly, a central tenet of this proposal is that adaptive changes in BDNF expression and function in specific brain regions as a consequence of chronic ethanol exposure and withdrawal experience plays a role in mediating and/or promoting excessive drinking associated with dependence. Our experimental strategy and approach for addressing this important research question involves use of our well- characterized mouse model of ethanol dependence and drinking. Proposed studies will examine the effects of repeated cycles of chronic ethanol exposure and withdrawal on time-dependent changes in Bdnf mRNA and BDNF protein expression in two brain structures intimately involved in ethanol dependence and drinking as well as BDNF-mediated behavioral effects: the prefrontal cortex (PFC) and the nucleus accumbens (NAc) (Aim I). A second set of studies will examine whether direct administration of BDNF into the PFC alters ethanol drinking in dependent compared to nondependent mice and whether this effect is selective for ethanol (Aim II). Studies also are proposed to investigate mechanisms underlying the ability of intra-PFC BDNF treatment to modulate ethanol drinking in our model of dependence and drinking (Aim III and Aim IV). These studies will focus on BDNF signaling mechanisms in the PFC and well as potential changes in BDNF activity in the NAc. Thus, this proposed research project will utilize our established mouse model of ethanol dependence and drinking to examine mechanisms by which neuroadaptive changes in BDNF expression and function contribute to escalation of drinking associated with ethanol dependence. As such, the proposal addresses a highly significant and clinically relevant research topic that will provide new information about potential therapeutic targets for treating ethanol dependence and harmful drinking associated with alcoholism.

Public Health Relevance

Alcohol abuse and dependence is a substantial problem for veterans, as it is for society at large. Thus, it is not surprising that the Department of Veterans Affairs has highlighted alcoholism as a special and high priority research area. Alcoholism is a chronic relapsing disease, and there is no therapeutic intervention that has proven to be fully satisfactory in battling the problem. Despite advancements in our understanding of how biological and environmental factors influence motivation to drink, the need for identifying new and novel mechanisms underlying dependence is key for development of more effective treatment strategies. This proposed research project will utilize a model of dependence and drinking to examine neurobiological mechanisms underlying excessive drinking associated with dependence. The overall goal is to provide new and valuable information that will aid in development of more effective treatments for individuals suffering from alcohol dependence and, thus, address an important and clinically relevant problem for our veteran patients.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000813-04
Application #
8696781
Study Section
Neurobiology A (NURA)
Project Start
2011-04-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Ralph H Johnson VA Medical Center
Department
Type
DUNS #
City
Charleston
State
SC
Country
United States
Zip Code
29401
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Lopez, Marcelo F; Miles, Michael F; Williams, Robert W et al. (2017) Variable effects of chronic intermittent ethanol exposure on ethanol drinking in a genetically diverse mouse cohort. Alcohol 58:73-82
Becker, Howard C (2017) Influence of stress associated with chronic alcohol exposure on drinking. Neuropharmacology 122:115-126
van der Vaart, Andrew D; Wolstenholme, Jennifer T; Smith, Maren L et al. (2017) The allostatic impact of chronic ethanol on gene expression: A genetic analysis of chronic intermittent ethanol treatment in the BXD cohort. Alcohol 58:93-106
Porcu, Patrizia; O'Buckley, Todd K; Lopez, Marcelo F et al. (2017) Initial genetic dissection of serum neuroactive steroids following chronic intermittent ethanol across BXD mouse strains. Alcohol 58:107-125
Anderson, Rachel I; Becker, Howard C (2017) Role of the Dynorphin/Kappa Opioid Receptor System in the Motivational Effects of Ethanol. Alcohol Clin Exp Res 41:1402-1418
Lopez, Marcelo F; Moorman, David E; Aston-Jones, Gary et al. (2016) The highly selective orexin/hypocretin 1 receptor antagonist GSK1059865 potently reduces ethanol drinking in ethanol dependent mice. Brain Res 1636:74-80
Anderson, Rachel I; Lopez, Marcelo F; Becker, Howard C (2016) Stress-Induced Enhancement of Ethanol Intake in C57BL/6J Mice with a History of Chronic Ethanol Exposure: Involvement of Kappa Opioid Receptors. Front Cell Neurosci 10:45
Lopez, Marcelo F; Anderson, Rachel I; Becker, Howard C (2016) Effect of different stressors on voluntary ethanol intake in ethanol-dependent and nondependent C57BL/6J mice. Alcohol 51:17-23
Smith, Maren L; Lopez, Marcelo F; Archer, Kellie J et al. (2016) Time-Course Analysis of Brain Regional Expression Network Responses to Chronic Intermittent Ethanol and Withdrawal: Implications for Mechanisms Underlying Excessive Ethanol Consumption. PLoS One 11:e0146257

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