Evidence from both preclinical studies and retrospective data from clinical trials indicate that opioid antagonists reduce alcohol drinking, especially continued alcohol drinking following lapse in drinking, as well as reduce craving for alcohol. However, the cascade of events that mediates this efficacy of opioid antagonists is still unknown. Increased knowledge of this mechanism may help to further understanding of the processes mediating continued alcohol drinking and result in the development of more effective treatments of alcohol dependence. Family history of alcoholism is known to be a significant risk factor for development of heavy alcohol drinking and understanding the biological basis of developing this genetic risk would also advance our ability to develop better treatments for this disorder. Our group has prospectively demonstrated using a laboratory paradigm of alcohol self-administration that naltrexone does indeed reducer alcohol consumption during an ad-libitum alcohol self-administration period following exposure to a priming drink of alcohol. We would now like to extend these findings to a laboratory model of relapse to alcohol that includes an alcohol deprivation period prior to the self-administration session. The results from this laboratory paradigm would more closely model evidence from clinical trials of naltrexone for alcohol dependence which indicate that one of the most important effects of naltrexone is to prevent relapse following a lapse of abstinence. The results of our self- administration paradigm also indicate that naltrexone induces HPA activation as evidenced by increased cortisol levels, that could either mediate naltrexone's effects or be a marker of naltrexone's efficacy. Recent evidence indicates that a genetic risk of alcoholism results in an attenuated release of cortisol in response to the opioid antagonist naloxone suggesting that the sensitivity of the endogenous opioid system to alcohol is altered by increased genetic risk. Therefore, we will conduct this study in heavy drinkers with or without a family history of alcoholism and address the following specific aims: 1) To evaluate the efficacy of six days of pretreatment with one of three doses of naltrexone (o,50 and 100 mg/day) using a laboratory model consisting of four days of alcohol deprivation following by exposure to a priming drink of alcohol and subsequent ad-libitum drinking and 2) To evaluate the influence of family history of alcoholism on the efficacy of naltrexone using a laboratory model consisting of four days of alcohol deprivation followed by exposure to a drinking drink of alcohol and subsequent ad- libitum alcohol drinking.
Showing the most recent 10 out of 273 publications
