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Uncoupling at the GABA(A) receptor with chronic ethanol in the rat medial septum/diagonal band (MS/DB)
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Functional tolerance to ethanol and physical dependence are thought to involve central nervous system (CNS) adaptive changes in the function of neurotransmitter systems which resist the initial intoxicating actions of ethanol. Increasing evidence suggests that the y-aminobutyric acid typeA(GABA,) receptor is one target of ethanol where such adaptive changes by the CNS may occur. Adaptation could occur by downregulation of GABAAreceptor number or uncoupling of the GABAAreceptor sensitivity to ethanol and related CNS depressants. These agents which show cross-tolerance and dependence with ethanol are allosteric modulators at the GABAAreceptor. Uncoupling is the decrease in the activity of an allosteric modulator at the receptor without a change in receptor number after prolonged exposure to either the agonist or allosteric modulator. Varying results have been obtained when looking at uncoupling at the GABAAreceptor with chronic drug treatment. The goal of this project was to determine-tine whether allosteric potentiation of GABAAreceptors by a benzodiazepine, a novel anticonvulsant or a neurosteroid is uncoupled by chronic ethanol treatment which may contribute to functional tolerance and physical dependence. Chronic ethanol was not found to induce an uncoupling of the potentiation seen with rnidazolam (0. I and 1. 0 liM), loreclezole (10 [uM), or allopregnanolone (0. I uM) to 3 uM GABA. However, the higher concentration of allopregnanolone (1.0 [uM) did show potentiation of the 3 uM GABA response in the chronically ethanol treated cells. In contrast, an increased potentiation was seen with midazolam (0. I uM) and GABA (0. I uM) in the ethanol treated cells. No potentiation was seen of 30 liM GABA response with any of the allosteric modulators tested. Therefore, it does not appear that chronic ethanol uncoupled potentiation of loreciezole or 0. I [uM allopregnanolone acting by general allosteric mechanisms. However, the higher (1 [uM concentration of allopregnanolone, which is thought to be capable of directly activating the GABAAreceptor, did show uncoupling of potentiation with cells chronically exposed to ethanol; this finding is consistent with an adaptive change in GABAAreceptor function.
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Includes bibliographical references: 63-70.
Issued also on microfiche from Lange Micrographics.
Wallace, Kathleen Allison (1997). Uncoupling at the GABA(A) receptor with chronic ethanol in the rat medial septum/diagonal band (MS/DB). Master's thesis, Texas A&M University. Available electronically from
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