Rodent studies suggest a link between stress, mesolimbic dopamine generation and abnormal reinforcement from drugs of abuse. It has been posited that the ability of stress to increase mesolimbic dopamine production results in sensitization of the reward pathway to drugs of abuse. Indeed, rats will consume more alcohol and other drugs following stress and post-stress alcohol drinking is attenuated by adrenalectomy. During the last funding period, we established that persons at increased risk for alcoholism (e.g., offspring of alcoholics) are more sensitive to Naloxone, have altered HPA axis dynamics and altered hypothalamic opioid activity, which can be identified before the onset of heavy drinking. Moreover, we had shown that chronic heavy drinking induces even more dramatic derangement in HPA axis dynamics, affecting mood and perhaps increasing the chances of relapse following withdrawal. Lastly, we showed that chronic Naltrexone administration blunted alcohol-induced activation of the HPA axis as well as blunting subjective """"""""liking"""""""" of alcohol """"""""high"""""""". We hypothesize that hypercortisolemia induced by alcoholism or family history of alcoholism alters mesolimbic dopamine production leading to abnormal reinforcement. The experiments outlined in this competitive renewal are a direct extension of our findings from the previous funding period. As well as interacting with 3 other RO-1 proposals through the IRPG, the experiments outlined in this application """"""""stand alone"""""""". Fist, we will extend our previous findings and determine if high- risk subjects have a more labile HPA axis in response to a psychological stress. Second, we will ascertain whether high cortisol reponders to Naloxone will also be high cortisol responders to """"""""real life"""""""" stress. Third, we will determine whether 1) family history of alcoholism, 2) personality measures or 3) anxiety measures interact to alter HPA axis dynamics. Fourth, using PET imaging, we will determine if high-risk nonalcoholics make more dopamine compared to low risk subjects. We will test the hypothesis that high cortisol secretors are also high dopamine releasers as the rodent literature predicts. Finally, 5 and 10-year follow-up studies will determine if high cortisol production or high dopamine release is independent risk factors for alcoholism.
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