Alcohol abuse continues to be a substantial medical and social problem in the United States. A complex interplay among numerous biological and environmental factors influences ETOH drinking behavior. Chronic excessive consumption of ETOH can lead to the development of dependence, and repeated experience with associated withdrawal episodes may constitute a powerful motivational force that perpetuates continued ETOH use/abuse, as well as contributing to relapse (i.e., the re-initiation of drinking after periods of abstinence). Given the high rate of recidivism in alcoholism, it is clear that relapse represents a major problem for most alcoholics, and relapse continues to represent a major challenge to treatment efforts. Currently, there is no therapeutic intervention (including pharmacotherapy) that is fully satisfactory in preventing relapse and sustaining abstinence. Thus, the development and use of preclinical models of ETOH relapse that closely approximate the clinical situation is essential for advancing investigations aimed at elucidating neural substrates and environmental circumstances that precipitate and/or mediate relapse, as well as facilitating the evaluation of more effective treatment strategies. The focus and overall objective of this proposal is to utilize a mouse model of repeated ETOH withdrawals and relapse to evaluate the efficacy of pharmacotherapies for relapse prevention, as well as identify molecular neurobiological events related to increased relapse susceptibility. Conceivably, changes in gene and protein expression that endure well beyond the presence of ETOH in the brain may represent key molecular adaptive events that are critical in mediating fundamental changes in brain function that define relapse susceptibility. Thus, it follows that identification of long-term changes in gene expression following repeated cycles of chronic ETOH exposure and withdrawal would provide valuable insight about potentially novel targets for new treatment approaches that are especially relevant to battling relapse. To date, there is very little information available about changes in gene expression that may relate to ETOH relapse. Therefore, a unique and novel feature of this proposal is to combine a robust behavioral model of ETOH relapse with sophisticated molecular techniques that involve applying gene arrays for identification of a 'relapse gene profile', followed by immunoblotting to validate the relevance of candidate changes. Further, identifying common molecular targets of pharmacotherapies for relapse prevention has the potential to lead to the development of new treatment strategies that are more effective than current ones in preventing relapse and sustaining abstinence. Thus, the aims and objectives of this proposal reflect an overarching experimental strategy that embodies a behavior-gene-behavior approach. The overall goal of this proposal is to utilize functional genomics/proteomics in a new model of ETOH relapse to evaluate, on a molecular level, the efficacy of various pharmacotherapies, as well as to identify new and novel targets for therapeutic intervention.
|Cui, Changhai; Noronha, Antonio; Warren, Kenneth R et al. (2015) Brain pathways to recovery from alcohol dependence. Alcohol 49:435-52|
|Melendez, Roberto I; McGinty, Jacqueline F; Kalivas, Peter W et al. (2012) Brain region-specific gene expression changes after chronic intermittent ethanol exposure and early withdrawal in C57BL/6J mice. Addict Biol 17:351-64|
|Griffin 3rd, William C; Lopez, Marcelo F; Yanke, Amy B et al. (2009) Repeated cycles of chronic intermittent ethanol exposure in mice increases voluntary ethanol drinking and ethanol concentrations in the nucleus accumbens. Psychopharmacology (Berl) 201:569-80|
|Griffin 3rd, William C; Lopez, Marcelo F; Becker, Howard C (2009) Intensity and duration of chronic ethanol exposure is critical for subsequent escalation of voluntary ethanol drinking in mice. Alcohol Clin Exp Res 33:1893-900|
|Becker, Howard C; Baros, Alicia M (2006) Effect of duration and pattern of chronic ethanol exposure on tolerance to the discriminative stimulus effects of ethanol in C57BL/6J mice. J Pharmacol Exp Ther 319:871-8|
|Lopez, Marcelo F; Becker, Howard C (2005) Effect of pattern and number of chronic ethanol exposures on subsequent voluntary ethanol intake in C57BL/6J mice. Psychopharmacology (Berl) 181:688-96|
|Becker, Howard C; Lopez, Marcelo F (2004) Increased ethanol drinking after repeated chronic ethanol exposure and withdrawal experience in C57BL/6 mice. Alcohol Clin Exp Res 28:1829-38|