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• W1988045452 abstract "Prolonged administration of anxiolytic, sedative, and anticonvulsant drugs that act through the GABAA receptor (GABAR) can evoke tolerance and dependence, suggesting the existence of an endogenous mechanism(s) for altering the ability of such agents to interact with the GABAAR. Uncoupling appears to be one such mechanism. This is a decrease in the allosteric interactions between the benzodiazepine (BZD) recognition site and other agonist or modulator sites on the GABAAR, as measured by potentiation of [3H]flunitrazepam ([3H]FNZ) binding. To investigate the mechanism(s) of uncoupling, neuronal cultures were treated chronically with 3α-hydroxy-5β-pregnan-20-one (pregnanolone), pentobarbital, flurazepam, or GABA, then tested for enhancement of [3H]FNZ binding by these substances. The results indicate that BZDs, barbiturates, and steroids, as well as GABA itself, are capable of inducing both heterologous and homologous uncoupling. Surprisingly, different chronic drug treatments produce different patterns of homologous and heterologous uncoupling. Chronic exposure to pregnanolone, GABA, flurazepam or pentobarbital induces complete uncoupling of barbiturate-BZD site interactions, partial uncoupling of GABA-BZD site interactions, but different amounts of uncoupling of steroid-BZD site interactions. In addition, the EC50 for pregnanolone-induced homologous uncoupling (1.7 μM) is over an order of magnitude greater than that for heterologous uncoupling of GABA and BZD sites (82 nM). Moreover, heterologous uncoupling by pregnanolone is inhibited by the GABA site antagonist SR-95531, whereas homologous uncoupling by pregnanolone is resistant to SR-95531. Therefore, there are at least two distinct ways in which GABAAR modulatory site interactions can be regulated by chronic drug treatment." @default.
• W1988045452 created "2016-06-24" @default.
• W1988045452 creator A5000768396 @default.
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• W1988045452 date "1996-01-01" @default.
• W1988045452 modified "2023-09-26" @default.
• W1988045452 title "γ-Aminobutyric acidA receptor regulation: heterologous uncoupling of modulatory site interactions induced by chronic steroid, barbiturate, benzodiazepine, or GABA treatment in culture" @default.
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• W1988045452 doi "https://doi.org/10.1016/0006-8993(95)01226-5" @default.
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