Alcohol (ethanol) addiction has been postulated to be due to formation of addictive alkaloidal derivativesfrom the interaction between biogenic amines and the ethanol metabolite, acetaldehyde. These tetrahydroisoquinoline alkaloids are also implicated in the cardiovascular and neurolgical side-effects of alcohol. The present investigation will gocus on two prinicpal objectives: (1) Elucidation of th cellular and subcellular mechanism(s) of stimulus- secretion coupling involved in acetaldehydeevoked release of adrenal catecholamines and their tetrahydroisoquinoline condensation products with acetaldehyde. The emphasis is on the role of extracellular and intracellular calcium in the secretory mechanism(s), and the possible identification of different mechanisms underlying release of catecholamines and their tetrahydroisoquinoline derivatives which would enable their separation by differential secretion. Pharmocological perfusion procedures and biochemical techniques for isolation of subcellular organelles by differential and discontinuous density gradient centrifugation will be emplyed. The bovine adrenal medulla will serve as the experimental model because of its established usefulness in the study of neuroendocrine release mechanisms. (2) A study of the pharmacological and toxicological profiles of the tetrahydroisoquinolines derived from "in tissue" (in situ) condensation of acetaldehyde and adrenal catecholamines. The rat will serve as the experimental model for in vivo studies, and emphasis will be on cardiovascular and central effects of the tetrahydroisoquinolines, particularly extrapyramidal facilitation an addiction liability. It is hoped that the results of this investigation will provide a better understanding of the toxicology of alcohol.l