Substantial evidence suggests that neurotensin, a tridecapeptide, is an important neuromodulator in the central nervous system. Neurotensin and its receptors are located in neurons projecting from the midbrain to forebrain and limbic structures, and central administration of this putative neurotransmitter produces pronounced effects on behavioral activity, thermoregulation, glucoregulation, and pain perception. Neurotensin potentiates the hypnotic action of ethanol in rats and differently enhances ethanol actions in short sleep (SS) but not in long sleep (LS) mice, selectively bred for differences in initial sensitivity to ethanol. There are similarities in behavioral and neurochemical actions to ethanol and neurotensin. 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 determine brain levels of neurotensin and effects of ethanol, in vivo, on neurotensin levels in LS and SS mice and will characterize neurotensin receptors and the effects of ethanol, in vitro, on receptors in brain regions of these mice. Since NT receptors appear to be coupled to production of the second messenger, 1,4,5-inositol trisphosphate, these studies will compare the effects of ethanol on NT receptor-coupled inositol phospholipid hydrolysis in LS and SS mice. Alcohol abuse and alcoholism continue to be a major health problem, and these studies will provide valuable information regarding the neurochemical basis for acute ethanol actions and for differential sensitivity to the effects of ethanol.
