GABAA receptor changes in acute allopregnanolone tolerance

Birzniece, Vita; Türkmen, Şahruh; Lindblad, Charlotte; Zhu, Di; Johansson, Ingvar; Bäckström, Torbjörn; Wahlström, Göran

doi:10.1016/j.ejphar.2006.01.059

Cited by 28 publications

(24 citation statements)

References 52 publications

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“…These phenomena could be described by different PK/PD models, reflecting more or less distinct underlying pharmacological or functional tolerance mechanisms. This is in line with the different receptor subtypes for which development of acute tolerance has been reported (Birzniece, et al, 2006;Holt, et al, 1996;Pericic, et al, 2007;van Rijnsoever, et al, 2004). In humans, it is difficult to relate specific GABA A receptor subtypes to certain functions, but some observations seem to support the associations among acute tolerance development, high α1-affinity, and sedation or postural instability.…”

Section: Discussionmentioning

confidence: 51%

Pharmacokinetics, pharmacodynamics and the pharmacokinetic/ pharmacodynamic relationship of zolpidem in healthy subjects

et al. 2009

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Zolpidem is one of the most frequently prescribed hypnotics, as it is a very short-acting compound with relatively few side effects. Zolpidem's short duration of action is partly related to its short elimination half-life, but the associations between plasma levels and pharmacodynamic (PD) effects are not precisely known. In this study, the concentration-effect relationships for zolpidem were modelled. Zolpidem (10 mg) was administered in a double-blind, randomised, placebo-controlled trial to determine PD and pharmacokinetics (PK) in 14 healthy volunteers. Zolpidem was absorbed and eliminated quickly, with a median T(max) of 0.78 h (range: 0.33-2.50) and t(1/2) of 2.2 h. Zolpidem reduced saccadic peak velocity (SPV), adaptive tracking performance, electroencephalogram (EEG) alpha power and visual analogue scale (VAS) alertness score and increased body sway, EEG beta power and VAS 'feeling high'. Short- and long-term memory was not affected. Central nervous system effects normalised more rapidly than the decrease of plasma concentrations. For most effects, zolpidem's short duration of action could be adequately described by both a sigmoid E(max) model and a transit tolerance model. For SPV and EEG alpha power, the tolerance model seemed less suitable. These PK/PD models have different implications for the mechanism underlying zolpidem's short duration of action. A sigmoid E(max) model (which is based on ligand binding theory) would imply a threshold value for the drug's effective concentrations. A transit tolerance model (in which a hypothetical factor builds up with time that antagonises the effects of the parent compound) is compatible with a rapid reversible desensitisation of GABAergic subunits.

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Section: Discussionmentioning

confidence: 51%

Pharmacokinetics, pharmacodynamics and the pharmacokinetic/ pharmacodynamic relationship of zolpidem in healthy subjects

et al. 2009

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“…Although there are several recently published data indicating that neuroactive steroids may have a tolerance liability similar to that of benzodiazepines [18][19][20], the mechanisms of tolerance development under chronic or repeated exposure to neuroactive steroids are not yet well-understood. However, it has been shown that neurosteroids not only interact with GABA A receptors but also down-regulate the expression of genes that encode the subunits of this receptor complex, reducing the sensitivity of the receptor to allosteric modulation [15,20].…”

Section: Discussionmentioning

confidence: 96%

“…However, it has been shown that neurosteroids not only interact with GABA A receptors but also down-regulate the expression of genes that encode the subunits of this receptor complex, reducing the sensitivity of the receptor to allosteric modulation [15,20].…”

Section: Discussionmentioning

confidence: 99%

The role of ovarian steroid hormones in the regulation of basal and stress induced absence seizures

Tolmacheva

Luijtelaar

2007

The Journal of Steroid Biochemistry and Molecular Biology

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“…Biochemical studies have demonstrated that the α4 and δ subunits are often present in the same receptor complex (Sur et al, 1999). Furthermore, α4βδ receptor expression has been shown to be very plastic in the CNS, with α4 protein levels subject to rapid regulation after administration of GABAergic drugs (Birzniece et al, 2006;Liang et al, 2007).…”

Section: Behavioural Phenotype Of Fmr1 Knockout Micementioning

confidence: 99%

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

et al. 2010

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The purpose of this study was to examine the expression of GABAergic proteins in Fmr1 knockout mice during brain maturation and to assess behavioural changes potentially linked to perturbations in the GABAergic system. Quantitative western blotting of the forebrain revealed that compared to wild-type mice, the GABA A receptor α1, β2, and δ subunits, and the GABA catabolic enzymes GABA transaminase and SSADH were down-regulated during postnatal development, while GAD65 was up-regulated in the adult knockout mouse forebrain. In tests of locomotor activity, the suppressive effect on motor activity of the GABA A β2/3 subunit-selective drug loreclezole was impaired in the mutant mice. In addition, sleep time induced by the GABA A β2/3-selective anaesthetic drug etomidate was decreased in the knockout mice. Our results indicate that disruptions in the GABAergic system in the developing brain may result in behavioural consequences in adults with fragile X syndrome.iii

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GABAA receptor changes in acute allopregnanolone tolerance

Cited by 28 publications

References 52 publications

Pharmacokinetics, pharmacodynamics and the pharmacokinetic/ pharmacodynamic relationship of zolpidem in healthy subjects

Pharmacokinetics, pharmacodynamics and the pharmacokinetic/ pharmacodynamic relationship of zolpidem in healthy subjects

The role of ovarian steroid hormones in the regulation of basal and stress induced absence seizures

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

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