While the effect of stress on ethanol consumption has been extensively studied in several animal models, these studies have yielded equivocal findings, with results depending on a myriad of factors including the type of stressor used, timing of stress presentation, initial ethanol preference, among many others. The INIAstress Consortium has contributed to this literature, mostly demonstrating that acute/sub-chronic administration of various stressors results in suppression of ethanol intake in various mouse models. In contrast, results from our laboratory have demonstrated that repeated cycles of chronic intermittent ethanol (CIE) exposure reliably produces escalation of voluntary ethanol drinking in C57BL/6J mice. Further, it has become evident that repeated cycles of CIE exposure constitutes a potent stressor itself, producing profound disturbances in neural and physiological systems. This has led to the overarching notion that chronic ethanol exposure and withdrawal experience produces persistent perturbations in neurophysiological systems within stress and reward circuits that tax the organism beyond normal homeostatic limits (i.e., a state of allostasis). These neuroadaptations are postulated to not only impact stress responsiveness, but also play a role in driving/promoting excessive levels of drinking associated with dependence. A major objective of this Mouse CIE Core is to provide comprehensive behavioral phenotypic evaluation of the effect of ethanol dependence (CIE exposure) and stress on voluntary ethanol intake in various genetic mouse models, as well as provide organ tissue samples (e.g., brain, plasma, adrenals) for use in other INIAstress projects. Specifically, studies conducted in this Core will focus on characterizing the effects of CIE exposure alone and in combination with various stress procedures on voluntary drinking in dependent and nondependent animals. These studies will be conducted with C57BL/6 mice, as well as unique mouse models that have been generated by the INIAstress Consortium, including BXD Rl strains and conditional (inducible) knockout mice with targeted gene deletions. This will provide critical information for guiding more in-depth analyses (endocrine, neurochemical, electrophysiological, genetic/genomic) in other research components of the INIAstress Consortium. In this way, the Core serves a centralized function in not only informing other projects about optimal experimental parameters regarding CIE/stress interactions in various mouse genotypes, but it also creates a framework that will facilitate integration of diverse research findings from various INIAstress projects relevant to the overall research theme and goals of the Consortium.

Public Health Relevance

Excessive alcohol consumption and alcoholism are major public health concerns. This Research Core serves a central function in the INAstress Consortium by providing valuable information and resources regarding stress-ethanol interactions that will not only inform and guide other research projects in the Consortium, but also provide the general field with novel and unique information that will advance our understanding about factors and mechanisms that promote excessive drinking. This is critical for development of new and more effective treatments for alcohol abuse and alcoholism.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAA1-DD (51))
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Grandison, Lindsey
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Medical University of South Carolina
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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
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
Nimitvilai, Sudarat; Lopez, Marcelo F; Mulholland, Patrick J et al. (2016) Chronic Intermittent Ethanol Exposure Enhances the Excitability and Synaptic Plasticity of Lateral Orbitofrontal Cortex Neurons and Induces a Tolerance to the Acute Inhibitory Actions of Ethanol. Neuropsychopharmacology 41:1112-27
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
Becker, H C; Lopez, M F (2016) An Animal Model of Alcohol Dependence to Screen Medications for Treating Alcoholism. Int Rev Neurobiol 126:157-77
Anderson, Rachel I; Lopez, Marcelo F; Becker, Howard C (2016) Forced swim stress increases ethanol consumption in C57BL/6J mice with a history of chronic intermittent ethanol exposure. Psychopharmacology (Berl) 233:2035-43
Rinker, Jennifer A; Fulmer, Diana B; Trantham-Davidson, Heather et al. (2016) Differential potassium channel gene regulation in BXD mice reveals novel targets for pharmacogenetic therapies to reduce heavy alcohol drinking. Alcohol :
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
Porcu, Patrizia; O'Buckley, Todd K; Lopez, Marcelo F et al. (2016) Initial genetic dissection of serum neuroactive steroids following chronic intermittent ethanol across BXD mouse strains. Alcohol :
Rose, Jamie H; Karkhanis, Anushree N; Chen, Rong et al. (2016) Supersensitive Kappa Opioid Receptors Promotes Ethanol Withdrawal-Related Behaviors and Reduce Dopamine Signaling in the Nucleus Accumbens. Int J Neuropsychopharmacol 19:

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