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.
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