This project is designed to study the effects of ethanol (ETOH) and aging alone and in combination on central cholinergic function of Fischer 344 rats. Both longitudinal and simultaneous experiments will examine basic cholinergic changes after ETOH and/or aging in rats obtained from breeding stock maintained under controlled conditions. The longitudinal studies will use rats at 4, 12, 20, and 28 months after the beginning of the study, whereas the simultaneous experiments will use the same aged rats timed for two individual studies in which rats of various ages will be studied at the same time. Basic information on central nervous system sensitivity, tolerance, physical dependence, blood ETOH levels, ETOH clearance and pathology will be gathered in rats of different ages given ETOH acutely or in short-term (20-day) or long-term (6-month) chronic ETOH exposure (Basic) studies. Other studies will examine whether central cholinergic changes occur in the cerebral cortex, hippocampus, corpus striatum, and brainstem of rats under conditions similar to those in the Basic studies. These studies will measure brain levels and turnover of acetylcholine (ACh) and are called Discovery studies. Following these, Begavuirak Correlate studies will determine time- and intensity-related changes in a novel behavioral fast reaction-time measure, in comparison with the neurochemical measures. Finally, the causes of ACh changes in the brain will be examined in Mechanism studies in which plasma choline, liver and brain phosphatidylcholine, synaptosomal choline uptake and muscarinic/nicotinic receptor measurements are followed under the same conditions as in the Basic study. Based upon available literature and pilot studies by the principal investigator, the proposed studies are likely to provide valuable information about central cholinergic changes during acute and chronic ETOH exposure, during aging, and during periods when ETOH interacts with the aging process.
