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• W2077813306 abstract "Long-term treatment with diazepam, a full allosteric modulator of the GABAA receptor, results in tolerance to its anticonvulsant effects, whereas an equipotent treatment with the partial allosteric modulator imidazenil does not produce tolerance. Use of subunit-specific antibodies linked to gold particles allowed an immunocytochemical estimation of the expression density of the α1, α2, α3, α5, γ2L&S and β2/3 subunits of the GABAA receptor in the frontoparietal motor and frontoparietal somatosensory cortices of rats that received long-term treatment with vehicle, diazepam (three times daily for 14 days, doses increasing from 17.6 to 70.4 μmol/kg), or imidazenil (three times daily for 14 days, doses increasing from 2.5 to 10.0 μmol/kg). In this study, tolerance to diazepam was associated with a selective decrease (37%) in the expression of the α1 subunit in layers III–IV of the frontoparietal motor cortex, and a concomitant increase in the expression of the α5 (150%), γ2L&S and β2/3 subunits (48%); an increase in α5 subunits was measured in all cortical layers. In the frontoparietal somatosensory cortex, diazepam-tolerant rats had a 221% increase in the expression of α5 subunits in all cortical layers, as well as a 35% increase in the expression of α3 subunits restricted to layers V–VI. Western blot analysis substantiated that these diazepam-induced changes reflected the expression of full subunit molecules. Rats that received equipotent treatment with imidazenil did not become tolerant to its anticonvulsant properties, and did not show significant changes in the expression of any of the GABAA receptor subunits studied, with the exception of a small decrease in α2 subunits in cortical layers V–VI of the frontoparietal somatosensory cortex. The results of this study suggest that tolerance to benzodiazepines may be associated with select changes in subunit abundance, leading to the expression of different GABAA receptor subtypes in specific brain areas. These changes might be mediated by a unique homeostatic mechanism regulating the expression of GABAA receptor subtypes that maintain specific functional features of GABAergic function in cortical cell layers." @default.
• W2077813306 created "2016-06-24" @default.
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• W2077813306 date "1997-05-01" @default.
• W2077813306 modified "2023-09-23" @default.
• W2077813306 title "Tolerance to diazepam and changes in GABAA receptor subunit expression in rat neocortical areas" @default.
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• W2077813306 doi "https://doi.org/10.1016/s0306-4522(96)00609-4" @default.
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