This application is a request to support ongoing projects in different stages of completion as well as those to be initiated. The principal objectives and specific aims of this research program during the proposed grant period (-05 through -08 years) are summarized as follows: First, studies will continue on the anatomical localization of specific sites in the brain which are selectively reactive to an amine-aldehyde condensation product or other neuroactive substance in terms of its mediation of a shift in alcohol self-selection. One structure thus far identified which mediates tetrahydropapaveroline (THP) - induced drinking of alcohol is the hippocampus. Experiments are being extended on the acute effect of different doses and volumes of alkaloid infusion as well as the regimen of chronic delivery to a site by means of an osmotic mini-pump. The anatomical structures include the nucleus reticularis paragigantocellularis (NRPG), periaqueductal gray (PAG), nucleus accumbens (NAC), ventromedial hypothalamus (VMH), and dorsal, ventral and other areas of the hippocampus. Second, systematic investigations will continue in which the attempt is made to either elevate alcohol drinking or attenuate it pharmacologically. Opiate receptor antagonists, an aldehyde dehydrogenase inhibitor, benzodiazepine receptor agonist or antagonist as well as other substances are administered directly into the brain to determine whether volitional alcohol intake can be modified in the test animal. Third, """"""""push-pull"""""""" perfusion procedures will be used for examining and characterizing in vivo chemical activity of circumscribed regions of the brain of the alcohol dependent animal. The kinetics of release of monoamines and their metabolites will be investigated.
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