The proposed research will test the hypothesis that some of the acute actions of ethanol are mediated by neurotensinergic processes and that individual differences in innate sensitivity to ethanol are governed, in part, by neurotensin receptor-coupled systems. These studies will characterize the high- and low-affinity receptors for neurotensin in several brain regions and will determine the effects of ethanol on processes coupled to these neurotensin receptors, specifically, phosphatidylinositol hydrolysis and neurotransmitter release.
Other specific aims i nclude using high performance liquid chromatography (HPLC) and radioimmunoassay to determine the effects of ethanol on neurotensin levels, in vivo, and on release of this neuropeptide from brain tissues, in vitro. Effects of ethanol on rate-limiting steps in neurotensin degradation by specific metalloendopeptidases will be measured by HPLC-mass spectrometry. These studies will utilize the long-sleep (LS) and short-sleep (SS) mice which have been genetically selected to differ in hypnotic sensitivity to ethanol and which have been shown to differ in response to low doses of ethanol, namely, locomotor activation. Genetic correlations between neurochemical parameters and behavioral effects of ethanol will be determined from experiments performed with the LSXSS recombinant inbred strains of mice. Alcoholism and alcohol abuse continue to be major health problems, and these studies will provide valuable information regarding the neurochemical basis for acute ethanol actions and for differential sensitivity to the effects of ethanol. Identification of the effects of ethanol on neurochemical processes, particularly in brain areas associated with the mesolimbic system, will assist in understanding mechanisms underlying the reinforcing effects of alcohol and thus its potential for abuse. Genetic differences in the effects of ethanol on these processes might account, in part, for the known genetic differences in susceptibility to alcoholism.
