To identify drugs that are likely to be efficacious at decreasing ethanol abuse, are specific to ethanol, and do not alter behaviors motivated by other reinforcing substances, animal models that closely approximate the human condition are necessary. This project proposes the use of an operant behavioral paradigm that allows for pharmacologically relevant levels of ethanol self-administration, that procedurally separates reinforcer-seeking from reinforcer drinking, and that uses two species of animals (rats and monkeys) in varying stages of ethanol experience. Experience will range from single daily drinking bouts (rats), to abusive consumption (monkeys), to ethanol-dependence (rats). The overall goal of this project is to develop and expand the behavioral paradigm that separately measures reinforcer-seeking and reinforcer consumption to test putative pharmacotherapies for the treatment of alcohol abuse with across-species studies. Three approaches will be utilized: 1) nondependent rats with daily, limited access to sucrose or ethanol, 2) ethanol-dependent rats made dependent in inhalation vapor chambers and tested in operant chambers, and 3) heavy ethanol-drinking monkeys with extended daily access to ethanol. Selectivity for ethanol will be determined by using a sweetened fluid as a control for drug effects on other types of reinforcer-motivated behaviors. Also, since the GABA(A) system has been implicated in the reinforcing and behavioral effects of ethanol, GABA(A) receptor ligands will be tested in this model. The profile of GABA(A) modulatory effects will be compared to the effects of two current pharmacotherapies (naltrexone and acamprosate). A """"""""successful pharmacotherapy"""""""" will decrease ethanol-seeking behavior and will be selective for ethanol with little to no effect on reinforced responding for the control fluid. Overall, the project allows for the comparison between dependent and nondependent subjects undergoing similar treatments, and the comparison between rats and monkeys in one laboratory. This project responds to 3 of the 5 areas of interest requested in the RFA: testing drugs with known pharmacological properties for therapeutic efficacy, developing a new animal model with high predictive validity, and further research on drugs currently used for the treatment of alcohol abuse.
