Robert D. Myers - US grants

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.

Historically, from the days of Feldberg in the 1950's, physiologists, pharmacologists, neurobiologists, neurochemists and other scientists have considered that the demonstration of the release of a neurotransmitter, and an alteration of its metabolism, served to reflect the neuronal function played by that substance. This proposed conference, to be sponsored by the New York Academy of Sciences, will present modern extensions of this historical perspective. It will provide noteworthy information on a series of remarkable findings that have arisen during the last decade, as well as on the burgeoning experimental observations that continuously emerge today. The conference on the neurochemical approaches and analysis of the brain of the conscious animal will make an exceedingly important contribution to the general fields of neuroscience and neurobiology. The reason for this viewpoint rests in the fact that a whole series of remarkable technical breakthroughs have occurred in several major scientific areas of endeavor. Today, in vivo analytical procedures are used at an ever-increasing rate to examine the actual on-line release, synthesis, metabolism and/or other activity on many endogenous factors in the brain, including neurotransmitters. To illustrate, an anatomically circumscribed site in the brain, in itself characterized by its chemical uniqueness, can be perfused or superfused by a physiological solution. As a result, a drug can be delivered in a controlled fashion to the site, and an endogenous factor can be collected from this tissue and identified by a quantitative assay. Alternatively, by the use of in vivo electrovoltammetry, the specific activity of a monoamine and certain of its metabolites can be delineated with a brain structure rich in content of the amine. Overall, the approaches that have yielded such extremely valuable information on the changes in brain chemistry that correlate with the physiological process, behavioral event, or a neuroendocrine response will constitute the major impact of this conference.