The abuse of ethanol leads to major social and medical problems, costing North American society billions of dollars yearly. Elucidation of the biological mechanisms of ethanol action, and of tolerance to it, would facilitate the development of rational and effective therapies for alcoholism. This research is intended to explore one basic action of ethanol, its facilitation of GABA-stimulated chloride ion flux across the nerve cell membrane, and its possible role in tolerance development. A quench-flow technique, that permits analysis of Cl- flux in isolated brain cell membrane preparations in a time scale measured in milliseconds rather than seconds, will be used to compare the effects of ethanol with those of barbiturates, benzodiazepines and general anesthetics, which share many of the pharmacological properties of ethanol in living organisms. These effects of alcohol in rat brain synaptoneurosomes will be correlated with a variety of behavioral effects of alcohol in the living rat, both on single exposure and during the course of development of tolerance by chronic administration. Since tolerance is known to be markedly affected by learning factors, this in vivo/in vitro correlation of alcohol tolerance will be studied in different models of tolerance with and without major influences of learning. Arginine vasopressin (AVP), a neurohormone produced in the hypothalamus, has been shown to maintain learned behaviors under conditions that otherwise favor extinction. AVP lso maintains behavioral tolerance to ethanol after ethanol administration is stopped; this effect of AVP is seen only if specific serotonin-containing nerve fibres running from the midbrain to the hippocampus are intact. If changes in chloride flux are central to ethanol tolerance, the interaction of AVP and serotonin (5-HT) should maintain them too, through membrane effects mediated by central vasopressin receptors. The types of AVP and 5-HT receptors involved in the maintenance of tolerance to ethanol will be identified, by correlating behavioral and biochemical data. Further, the second messenger systems mediating the actions of these receptors will also be identified. The activation of second messenger systems, which leads to increased protein phosphorylation and alterations in cellular function, may modulate tolerance development. An understanding of these processes will aid the development of specific agents capable of modifying or maintaining ethanol tolerance.
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