While stress is known to be an important contributing factor to alcohol abuse and alcoholism, the interaction between stress and ethanol drinking behavior, as well as mechanisms underlying this interaction in the context of dependence are not well understood. Prolonged ethanol exposure constitutes a potent stressor, producing a state of allostasis whereby chronic intoxication continually taxes the organism beyond normal homeostatic limits, rendering it ill-equipped to exert appropriate behavioral control over ethanol consumption, as well as appropriately respond to other (additional) stressful events that may provoke return to excessive drinking. During the current funding period, we have used a mouse model of chronic intermittent ethanol (CIE) exposure to demonstrate that resulting significant escalation of drinking is associated with profound alterations in neuroendocrine-related (HPA axis activity) and independent (extrahypothalamic corticotropin releasing factor, CRF) stress systems. However, mechanisms underlying dependence-related alterations in stress responsiveness and, in particular, the ability of stress to modulate drinking in the context of dependence have not been extensively studied. Accordingly, this proposal will build and expand on our current work by utilizing our CIE model of dependence to examine the role of CRF and CRF1 receptor activity in brain regions within cortical-limbic-HPA circuitry (brain structures and pathways integral to stress and reward/motivational processes) that mediate/contribute to: (a) escalation of ethanol drinking in dependent mice;(b) altered (compromised) behavioral responsiveness to stress challenge;and (c) the ability of stress to modulate ethanol consumption in dependent compared to nondependent mice. A unique feature of this proposal is use of various tools and approaches in examining behavioral, physiological, neurochemical, and molecular responses to stress overlaid on the CIE model. As such, this project not only fills a void in the literature related to ethanol dependence and stress, but importantly, it targets the major overarching theme of the INIA-Stress Consortium as well as complements other projects with a similar research focus in the Consortium. The overall goal of the project is to provide a more comprehensive understanding of neuroadapfive changes in CRF funcfion that underlie stress-ethanol interactions in the context of dependence, and gain a better understanding of how such changes contribute to excessive and harmful drinking behavior as well as the development of alcoholism.
Alcoholism is a major health concern as well as a significant social and economic burden on society in the U.S., and stress is known to contribute to the problem. This research project aims to enhance our understanding about mechanisms by which stress associated with alcohol dependence promotes excessive drinking. The goal is to facilitate development of new and more effective treatment strategies for alcohol abuse and alcoholism.
|Harlan, Benjamin A; Becker, Howard C; Woodward, John J et al. (2018) Opposing actions of CRF-R1 and CB1 receptors on VTA-GABAergic plasticity following chronic exposure to ethanol. Neuropsychopharmacology 43:2064-2074|
|Osterndorff-Kahanek, Elizabeth A; Tiwari, Gayatri R; Lopez, Marcelo F et al. (2018) Long-term ethanol exposure: Temporal pattern of microRNA expression and associated mRNA gene networks in mouse brain. PLoS One 13:e0190841|
|Haun, Harold L; Griffin, William C; Lopez, Marcelo F et al. (2018) Increasing Brain-Derived Neurotrophic Factor (BDNF) in medial prefrontal cortex selectively reduces excessive drinking in ethanol dependent mice. Neuropharmacology 140:35-42|
|Rodberg, Ellen M; den Hartog, Carolina R; Anderson, Rachel I et al. (2017) Stress Facilitates the Development of Cognitive Dysfunction After Chronic Ethanol Exposure. Alcohol Clin Exp Res 41:1574-1583|
|Becker, Howard C (2017) Influence of stress associated with chronic alcohol exposure on drinking. Neuropharmacology 122:115-126|
|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|
|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|
|Siciliano, Cody A; Locke, Jason L; Mathews, Tiffany A et al. (2017) Dopamine synthesis in alcohol drinking-prone and -resistant mouse strains. Alcohol 58:25-32|
|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|
|Laguesse, Sophie; Morisot, Nadege; Shin, Jung Hoon et al. (2017) Prosapip1-Dependent Synaptic Adaptations in the Nucleus Accumbens Drive Alcohol Intake, Seeking, and Reward. Neuron 96:145-159.e8|
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