The forebrain opiomelancortinergic system originates in the mediobasal hypothalamus (MBH) and produces neuropeptides derived from pro-opiomelanocortin, including the potent opioid B-endorphin (BEND). Alcohol, cocaine, nicotine, and tetrahydrocannabinol alter brain BEND concentrations and opioid receptor binding, and opioid receptor antagonists decrease reinforcement by these same drugs. Thus, some responses to varied drugs of abuse are likely mediated by common B-endorphinergic mechanisms. Brain B-endorphinergic activity modulates psychomotor stimulation, reinforcement, pain, eating, sexual behavior, pituitary function, and immune function, so this mechanisms may have an important central role in varied responses to drugs. Two other systems also have key integrating roles in mediating/modulating behavioral and neuroendocrine responses to ethanol and other drugs of abuse - the hypothalamic-pituitary-adrenal (H-P-A) and mesolimbic dopaminergic systems. Compelling evidence suggests the forebrain opiomelanocortinergic neuronal system and the HPA axis may be functionally interdependent, and may have critical roles in modulating the mesolimbic dopaminergic system. Our ultimate goal is to resolve the roles that interactions between these three key systems play in mediating responses to alcohol and other drugs of abuse revealing potential treatments, interventions, and predictive indices of abuse potential. Our immediate goal is to address interactions between just two, the forebrain opiomelanocortinergic system and the HPA axis. Our current specific aims are to answer the following questions, using a rat model. (1) Do individuals with increased HPA sensitivity to alcohol also exhibit increased forebrain opiomelanocortinergic responses to alcohol? (2) Does elective self-administration of reinforcing dosages of alcohol in the context of normal alcohol use stimulate HPA and forebrain opiomelanocortinergic activity? (3) Do chronic high dose episodes of alcohol consumption and withdrawal induce chronic changes in the HPA and forebrain opiomelanocortinergic systems independent of other stressors such as malnutrition or chronic hunger? These specific aims will be addressed by determining opiomelanocortinergic responses as reflected by changes in hypothalamic pro-opiomelanocortin gene expression, peptide content and post-translational processing and monitoring HPA responses by determining hypothalamic corticotropin-releasing factor (CRF) gene expression and radioimmuno-assay (RIA) of ACTH and corticosterone in plasma.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
2R01AA010567-03A1
Application #
2614837
Study Section
Special Emphasis Panel (ZRG4-ALTX-3 (01))
Project Start
1994-07-01
Project End
2002-04-03
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
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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