Articles: gaba-modulators-pharmacology.
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J. Pharmacol. Exp. Ther. · Jun 2000
Enantioselectivity of pregnanolone-induced gamma-aminobutyric acid(A) receptor modulation and anesthesia.
This study reports the actions of enantiomer pairs of anesthetic steroids 3alpha5alphaP/ent-3alpha5alphaP and 3alpha5betaP/ent-3alpha5betaP as modulators of gamma-aminobutyric acid (GABA)(A) receptors and as anesthetics. The enantiomers of structurally related 17-carbonitrile analogs also are examined. These studies were aimed at 1) determining whether the steroid recognition site could distinguish between molecules differing in shape, but not other physical properties (enantioselectivity); 2) providing further insight into the structure-activity relationships of anesthetic steroids; and 3) determining whether modulation of GABA(A) receptor function correlates with anesthetic potency for anesthetic steroid enantiomers. ⋯ For all compounds studied, the effects on GABA(A) receptor function closely tracked with anesthetic effects. These data show that the anesthetic steroid recognition site is capable of distinguishing enantiomers, suggesting a protein-binding site of specific dimensions and shape. The results are compatible either with a structural model of the binding site that can accommodate 3alpha5alphaP, 3alpha5betaP, and ent-3alpha5betaP, but not ent-3alpha5alphaP, or with two different binding sites for steroid anesthetics.
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British dental journal · Mar 2000
Randomized Controlled Trial Clinical TrialThe effects of midazolam and flumazenil on psychomotor function and alertness in human volunteers.
To investigate the effect of midazolam and flumazenil on psychomotor function and alertness in human volunteers. ⋯ An earlier discharge time based on subjective assessment of alertness is not advocated for patients whose intravenous midazolam sedation is reversed with flumazenil.
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Although intrathecal administration of midazolam has been found to produce analgesia, how midazolam exerts this effect is not understood fully at the neuronal level in the spinal cord. ⋯ Midazolam augmented both the duration of GABA-mediated synaptic current and the amplitude of GABA-induced current by acting on the GABA(A)-benzodiazepine receptor in substantia gelatinosa neurons; this would increase the inhibitory GABAergic transmission. This may be a possible mechanism for antinociception by midazolam.
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Comparative Study
Activation of rat locus coeruleus neuron GABA(A) receptors by propofol and its potentiation by pentobarbital or alphaxalone.
The action of propofol on the rat locus coeruleus was examined using intracellular recording from in vitro brain slice preparations. Concentrations of propofol between 3 and 300 microM were tested. At 100 microM, propofol completely inhibited the firing of all neurons tested (n=34); this was associated with a 5.7-mV hyperpolarization (range 0-16 mV, n=33) and a 35.6% reduction in input resistance (range 7.3-66.1%, n=33). ⋯ In contrast, diazepam caused no potentiation of either propofol- or GABA-induced responses. Our data also indicate that locus coeruleus neuron GABA(A) receptors possess distinctive pharmacologic characteristics, such as blocking of the propofol effects by zinc and insensitivity to diazepam and the direct action of pentobarbital. On the basis of these pharmacologic properties, we suggest that locus coeruleus neuron GABA(A) receptors do not contain the gamma subunit.
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The effect of diabetes on the effect of diazepam on the propofol-induced loss of the righting reflex was investigated. There was no significant difference in the duration of the propofol-induced loss of the righting reflex between non-diabetic and diabetic mice. Diazepam increased the duration of the propofol-induced loss of the righting reflex in both diabetic and non-diabetic mice. ⋯ These effects were antagonized by the pretreatment with flumazenil. Pretreatment with FG7142, a benzodiazepine receptor inverse agonist, attenuated the duration of the propofol-induced loss of the righting reflex in non-diabetic mice, but not in diabetic mice. These results suggest that the attenuation of the diazepam-induced enhancement of the duration of the propofol-induced loss of the righting reflex in diabetic mice may be due to the dysfunction of benzodiazepine receptors.