We have developed a rat model in which chronic daily ethanol consumption/daily withdrawal induces hypothalamo-pituitary-adrenal (HPA), brain proopiomelanocortin (POMC) opioid, behavioral (e.g., anxiety), sympathoadrenal and metabolic changes persisting long (at least 4 weeks) after stopping ethanol consumption. These changes are functionally interdependent and have each been individually suggested to contribute to alcoholism. Furthermore, this overall HPA+POMC+sympathoadrenal+metabolic+behavioral (HPSMB) 'syndrome' is consistent with characteristics exhibited by abstinent alcoholics, ethanol-preferring rat strains, non-alcoholic individuals with familial propensity to alcoholism, and post-traumatic stress disorder (PTSD) patients highly prone to ethanol abuse. The long-lasting post-ethanol changes in these interdependent functions thus likely play important roles in ethanol dependence and/or relapse.
Specific Aim 1 is to determine the time course and identify potential mechanisms for the HPSMB syndrome, using our well-characterized and reproducible daily ethanol consumption/withdrawal model. These investigations will include evaluating diurnal changes, duration, and delayed expression of responses.
Specific Aim 2 is to determine whether investigator-administered versus elective ethanol self-administration alters induction of the HPSMB syndrome.
Specific Aim 3 is assess the likely role of the HPSMB syndrome in producing the alcohol deprivation effect. To achieve these aims, changes associated with the HPSMB syndrome will be assessed as behavioral (anxiety), endocrine, in vitro, and brain and pituitary gene expression responses characteristic of, consistent with, or contributing to alcohol abuse and relapse.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Neurotoxicology and Alcohol Study Section (NAL)
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Grandison, Lindsey
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University of Washington
Schools of Medicine
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Rasmussen, Dennis D; Kincaid, Carrie L (2015) Acoustic startle in alcohol-naïve male rats predicts subsequent voluntary alcohol intake and alcohol preference. Alcohol Alcohol 50:56-61
Rasmussen, Dennis D; Alexander, Laura; Malone, Julia et al. (2014) The ?2-adrenergic receptor agonist, clonidine, reduces alcohol drinking in alcohol-preferring (P) rats. Alcohol 48:543-9
Rasmussen, Dennis D; Alexander, Laura L; Raskind, Murray A et al. (2009) The alpha1-adrenergic receptor antagonist, prazosin, reduces alcohol drinking in alcohol-preferring (P) rats. Alcohol Clin Exp Res 33:264-72
Rasmussen, Dennis D; Crites, Norman J; Burke, Brianna L (2008) Acoustic startle amplitude predicts vulnerability to develop post-traumatic stress hyper-responsivity and associated plasma corticosterone changes in rats. Psychoneuroendocrinology 33:282-91
Rasmussen, Dennis D; Wilkinson, Charles W; Raskind, Murray A (2006) Chronic daily ethanol and withdrawal: 6. Effects on rat sympathoadrenal activity during ""abstinence"". Alcohol 38:173-7
Puchalski, Stephaney S; Green, Jill N; Rasmussen, Dennis D (2003) Melatonin effects on metabolism independent of gonad function. Endocrine 21:169-73
Rasmussen, Dennis D; Sarkar, Dipak K; Roberts, James L et al. (2003) Chronic daily ethanol and withdrawal: 4. Long-term changes in plasma testosterone regulation, but no effect on GnRH gene expression or plasma LH concentrations. Endocrine 22:143-50
Rasmussen, Dennis D (2003) Chronic daily ethanol and withdrawal: 5. Diurnal effects on plasma thyroid hormone levels. Endocrine 22:329-34
Puchalski, Stephaney S; Green, Jill N; Rasmussen, Dennis D (2003) Melatonin effect on rat body weight regulation in response to high-fat diet at middle age. Endocrine 21:163-7
Rasmussen, Dennis D; Marck, Brett T; Boldt, Brian M et al. (2003) Suppression of hypothalamic pro-opiomelanocortin (POMC) gene expression by daily melatonin supplementation in aging rats. J Pineal Res 34:127-33

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