The proposed experiments utilize a C5713L/6 (B6) murine model to determine if gender and/or estrus state influence the response to ethanol and ethanol conditioned stimuli or influence the impact of potential therapeutic agents on the response to ethanol-related stimuli. Although both positive and negative reinforcing stimuli regulate behavior directed toward obtaining and consuming ethanol and other abused drugs, we focus on evaluating the influence of gender on the effect on the positive reinforcing stimuli related to ethanol. Such information is basic and applicable to conditions reflective of """"""""craving"""""""", """"""""loss of control"""""""", or """"""""relapse after abstinence"""""""", all of which have ethanol-related stimuli as a component. Although female members of our society contribute to the alcoholic population, preclinical investigations on potential therapeutic agents focus almost exclusively on young male rats. The general hypothesis guiding the proposed research is that gender and estrus state will (1) influence the rewarding effects of ethanol and ethanol -conditioned stimuli and (2) influence the ability of potential therapeutic agents to reduce the reward value of these stimuli. The strategy for testing this hypothesis is to compare the impact of ethanol-related stimuli in male and female mice as well as female mice during two distinct stages of estrus. The effect of estrus cycle on the effect of potential therapeutic agents (Naltrexone, Onclansetron, Vigabatrin) will be measured using behavioral evaluations of the rewarding effects of ethanol and ethanol-conditioned stimuli. Opioid antagonists (Naltrexone) 5-HT3 antagonists (Ondansetron) and GABA transaminase inhibitors (Vigabatrin) have all been shown to attenuate the rewarding effects of ethanol in male monkeys, rats, and mice and can also reduce the rewarding effects of ethanol-conditioned stimuli in male rats and mice. Whether effects on female members of the different species follow those noted for males is unknown, and is the focus of this proposal. An important aspect of the proposed work is to establish whether the drugs can attenuate the rewarding effects of ethanol and ethanol-conditioned stimuli with few unwanted side effects in female mice as we have demonstrated for male mice. Although the experiments are for ethanol reward, they should be generalized to treatment in paradigms for other drugs of abuse such as cocaine, heroin and morphine.
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