Maintaining abstinence in recovering alcohol dependent patients is difficult. Often, sampling of alcohol by these individuals frequently leads to a loss of control that precipitates a relapse. The use of naltrexone as a pharmacological adjunct to the psychosocial treatment program has recently been shown to significantly reduce these relapse rates (O'Malley et al., 1992; Volpicelli et al., 1992). The mechanism by which naltrexone achieves this effect remains unclear, but some evidence from animal models suggests that it may do so by preventing the ethanol-induced release of dopamine in the mesolimbic positive reinforcing pathways (Benjamin et al., 1992; Widdowson and Holman, 1992). These pathways have been implicated in the positive reinforcing properties of many drugs of abuse, including ethanol (Koob, 1992). While the initial evidence implicating endogenous opioids as a potential modulator of dopamine reinforcement pathways is interesting, many questions remain to be answered. For example, it is not completely clear what contribution is made by specific types of opioid receptors. If, for example, delta antagonism is the critical factor in reducing excessive alcohol drinking, then specific delta antagonists would offer an advantage in the clinical treatment of alcohol dependence. These drugs would have fewer side effects and patients would be able to obtain pain relief from mu agonists. This proposal seeks training in microdialysis so that I can continue my investigation of the neuropharmacological properties of ethanol and how these may relate to those reinforcing properties that maintain consumption. Specifically, microdialysis will permit the assessment of extracellular levels of dopamine and serotonin in the nucleus accumbens resulting from both experimenter administered acute ethanol and chronic self-administered ethanol in rats. It will also allow for the comparison of the effectiveness of themu and delta selective opioid antagonists, beta- funaltrexamine and naltrindole, to the nonselective antagonist, naltrexone, on both the behavioral measure of consumption and the neurochemical measures. Because conditioned drug effects are often responsible for increases in craving that lead to relapse, the effects of these opioid antagonists on extracellular dopamine and serotonin in the nucleus accumbens produced by exposure to drug associated cues will also be compared. This research is designed to advance our knowledge of how opioid antagonists help protect against relapse in recovering alcohol dependent patients. In addition, it seeks to determine if other pharmacological interventions, such as a mu or delta selective antagonist, would be more effective than the nonselective opioid antagonist, naltrexone. Further, it will provide me with the training in microdialysis necessary to advance my ability to study the neuropharmacological changes related to the reinforcing properties of ethanol.
| Stromberg, Michael F; Mackler, Scott A (2005) The effect of cocaine on the expression of motor activity and conditioned place preference in high and low alcohol-preferring Wistar rats. Pharmacol Biochem Behav 82:314-9 |
| Kim, Sung-Gon; Han, Byeung-Deuk; Park, Je-Min et al. (2004) Effect of the combination of naltrexone and acamprosate on alcohol intake in mice. Psychiatry Clin Neurosci 58:30-6 |
| Stromberg, M F; Mackler, S A; Volpicelli, J R et al. (2001) Effect of acamprosate and naltrexone, alone or in combination, on ethanol consumption. Alcohol 23:109-16 |
| Kim, S G; Stromberg, M F; Kim, M J et al. (2000) The effect of antagonists selective for mu- and delta-opioid receptor subtypes on alcohol consumption in C57BL/6 mice. Alcohol 22:85-90 |
| Rukstalis, M R; Stromberg, M F; O'Brien, C P et al. (2000) 6-beta-naltrexol reduces alcohol consumption in rats. Alcohol Clin Exp Res 24:1593-6 |
