Articles: gaba-modulators-pharmacology.
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J. Pharmacol. Exp. Ther. · Sep 1997
Allopregnanolone affects sleep in a benzodiazepine-like fashion.
Recent research in rats and humans has shown that exogenous progesterone evokes a sleep profile similar to that induced by agonistic modulators of gamma-aminobutyric acid(A) receptors, such as benzodiazepines. This finding suggests the involvement of the neuroactive metabolite of progesterone, allopregnanolone. In the vehicle-controlled study reported here, we assessed the sleep effects of two doses of allopregnanolone (7.5 and 15 mg/kg), mixed with oil, administered intraperitoneally at light onset in 8 rats. ⋯ Analysis of the plasma and brain concentrations of allopregnanolone in 45 rats revealed long-lasting increases, which reached maximal levels during the first postinjection hour. The sleep effects of allopregnanolone are very similar to those elicited by larger doses of progesterone, which produce comparable brain levels of allopregnanolone. These data indicate that the steroid allopregnanolone has benzodiazepine-like effects on sleep.
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Molecular pharmacology · Nov 1996
Pharmacology of the human gamma-aminobutyric acidA receptor alpha 4 subunit expressed in Xenopus laevis oocytes.
The human gamma-aminobutyric acidA (GABAA) receptor alpha 4 subunit was recently cloned and characterized pharmacologically using radioligand binding techniques. These studies suggested that alpha 4 subunits confer a novel diazepam-insensitive binding site. To further investigate the pharmacology of the alpha 4 subunit, we expressed human alpha 4 beta 2 gamma 2L subunit combinations in oocytes and compared the expression and pharmacology of these receptors with alpha 1 beta 2 gamma 2L, beta 2 gamma 2L, and other possible binary subunit combinations. ⋯ The pharmacology conferred by the alpha 4 subunit was similar to that conferred by the alpha 6 subunit, to which it shows highest levels of homology, but the two subunits differ in sensitivity to the beta-carboline methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate. Properties of the alpha 4-containing receptors are consistent with diazepam-insensitive binding sites found in cerebral cortex and other forebrain structures. Characterization of these receptors should further our understanding of mechanisms underlying the behavioral effects of GABA modulators and help in the design of drugs with improved, or novel, therapeutic profiles.
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Randomized Controlled Trial Comparative Study Clinical Trial
A pilot pharmacokinetic-pharmacodynamic study of benzodiazepine antagonism by flumazenil and aminophylline.
To develop a pharmacokinetic-pharmacodynamic model using quantitative electroencephalographic (EEG) analysis to compare two separate benzodiazepine antagonists and generate data concerning response variability. ⋯ Flumazenil was consistently effective in reversing sedation by midazolam at routinely recommended dosing. Further investigation of aminophylline as a reversal agent should use an estimated dose of 6-8 mg/kg aminophylline. To achieve adequate reversal, some patients may require aminophylline dosages that exceed safe clinical administration.
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Recent investigations in the authors' laboratory have shown that acute tone exposure (4 kHz continuous tone, 104 dB sound pressure level (SPL), 30-min duration) induces increases in the amplitude of click-evoked potentials in the inferior colliculus (IC). These increases have been attributed to a decrease in GABAA-mediated inhibition on IC neurons. In the present study, we examined the effects of three compounds (diazepam, clonazepam, and (-)-baclofen) that are known to enhance GABAergic inhibition on these tone exposure-induced increases and on changes in temporal integration in the IC. (-)-Baclofen was the only one of the three compounds tested that reversed in a dose-dependent manner the effects of tone exposure on both the amplitude of the click-evoked potentials recorded from the IC and on measures of the changes in temporal integration based on these potentials. ⋯ The results of this study show that (-)-baclofen is a potent modulator of both the excitability of neurons in the ascending auditory pathway and the processing of auditory information by IC neurons. The finding of the present study that two benzodiazepines (clonazepam and diazepam) have remarkably different effects on evoked potentials, which reflects both input to the IC and postsynaptic events in the IC neurons, suggests heterogenicity of the GABAA receptor from one structure to another in the ascending auditory pathway. We suggest that (-)-baclofen may be clinically useful in treating disorders of the auditory system that are caused by plasticity in the ascending auditory pathway.
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1. Chronic benzodiazepine treatment of rat cerebellar granule cells induced a transient down-regulation of the gamma-aminobutyric acidA (GABAA) receptor alpha 1 subunit protein, that was dose-dependent (1 nM-1 microM) and prevented by the benzodiazepine antagonist flumazenil (1 microM). After 2 days of treatment with 1 microM flunitrazepam the alpha 1 subunit protein was reduced by 41% compared to untreated cells, which returned to, and remained at, control cell levels from 4-12 days of treatment. ⋯ This study has shown that both flunitrazepam and GABA treatment, via their respective binding sites, caused a reduction in the expression of the GABAA receptor alpha 1 subunit protein; an effect mediated through the same neurochemical mechanism. The results also imply that the benzodiazepine effect is independent of GABA, and that the benzodiazepine and GABA sites may not be equally coupled to the down-regulation process, with the benzodiazepine site being the more dominant. The biochemical mechanism underlying the benzodiazepine-mediated down-regulation of the alpha 1 subunit protein seems to involve the activity of staurosporine-sensitive protein kinases.