Toward unifying hypotheses for the cause of alcohol-associated disease, major efforts have centered on: (1) metabolic changes associated with ethanol catabolism, and (2) physical disordering of cellular membranes by ethanol with resulting alterations in membrane function. This proposal focuses on the latter or """"""""membrane hypothesis"""""""" of alcohol action to study both acute and chronic effects of ethanol on synaptic membrane function in the central nervous system (CNS). Ethanol is among the mostly commonly abused psychotropic drugs and abstinence after chronic use leads to withdrawal symptoms that constitute physical dependence. Altered neural activity associated with gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain, and the postsynaptic GABA/benzodiazepine receptor complex has been implicated in both acute and chronic effects of ethanol in the CNS. Isolated nerve ending preparations (synaptosomes) from adult rat brain will be employed to study presynaptic effects of ethanol on the GABA transport system. Rats will be fed normal rat chow or liquid diets containing alcohol or isocaloric carbohydrate to determine acute and chronic effects of ethanol on this transport system which controls the steady-state and dynamic concentrations of GABA in the synapse. Evidence is presented that ethanol can potentiate or inhibit GABAergic activity by dose-dependent alterations in this presynaptic system. Mechanisms to be investigated involve several interacting membrane components including the GABA transport protein, Na+, K+-ATPase (the driving force for the transport), ATPase-modulating peptide(s), and the lipids surrounding these components in the synaptic membrane. Of particular interest is the observation that the presence or absence of an easily extractable protein(s) defines whether ethanol is stimulatory or inhibitory (in the physiological concentration range) to the Na+, K+-ATPase and, thereby, to transport of GABA. The amount and disposition of such an """"""""ethanol-modifying factor"""""""" in the membrane could be a genetically- determined component accounting for individual variability in response to alcohol use/abuse. Such studies are needed to elucidate neurochemical bases for alcohol intoxication and dependence. This will both promote understanding of the associated-diseases and identify critical functional components of synaptic membranes that are altered by ethanol use/abuse and to which treatment might be directed.
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