Acute Tolerance to Diazepam in Mice: Pharmacokinetic Considerations

Yoong, Y. L.; Lee, H. S.; Gwee, M.C.E.; Wong, Peter T.-H.

doi:10.1111/j.1440-1681.1986.tb00329.x

Cited by 10 publications

(9 citation statements)

References 12 publications

(6 reference statements)

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“…To elucidate further the importance of these phenomena, the concentration-EEG effect relationship of midazolam was studied after various rates and routes of drug administration. Acute tolerance is reported to develop towards several actions of benzodiazepines in man (MacLeod et al, 1977;Ellinwood et al, 1983; and animals (Yoong et al, 1986;File et al, 1989). It has been suggested that the rate of drug administration is an important determinant of the clinical effects of benzodiazepines and development of acute tolerance (Greenblatt et al, 1977;Grundstrom et al, 1978;Sellers, 1978;Ellinwood et al, 1985).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic‐pharmacodynamic modelling of the EEG effects of midazolam in individual rats: influence of rate and route of administration

Mandema

Tukker

Danhof³

1991

British J Pharmacology

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic‐pharmacodynamic modelling of the EEG effects of midazolam in individual rats: influence of rate and route of administration

Mandema

Tukker

Danhof³

1991

British J Pharmacology

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“…Finally, we wanted to determine if similar mechanisms occur in vivo following DZP treatment. Prior publications show that BZDs and metabolites are not present 24 h post-injection due to rapid drug metabolism in rodents (41)(42)(43)(44). Furthermore, BZD uncoupling does not persist 24 h after a single dose (15 mg/kg) or 2 week daily DZP treatment, whereas uncoupling can be seen 12 h after a single injection, indicating this is the appropriate timepoint for measuring in vivo loss of γ2-GABA A R function (4).…”

Section: Dzp Exposure Modifies γ2-gaba a R And Gephyrin Levelsmentioning

confidence: 99%

Diazepam Accelerates GABAAR Synaptic Exchange and Alters Intracellular Trafficking

Lorenz-Guertin

Bambino

Das

et al. 2019

Preprint

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Despite 50+ years of clinical use as anxiolytics, anti-convulsants, and sedative/hypnotic agents, the mechanisms underlying benzodiazepine (BZD) tolerance are poorly understood. BZDs potentiate the actions of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the adult brain, through positive allosteric modulation of γ2 subunit containing GABA type A receptors (GABA A Rs). Here we define key molecular events impacting γ2 GABA A R and the inhibitory synapse gephyrin scaffold following initial sustained BZD exposure in vitro and in vivo. Using immunofluorescence and biochemical experiments, we found that cultured cortical neurons treated with the classical BZD, diazepam (DZP), presented no substantial change in surface or synaptic levels of γ2-GABA A Rs. In contrast, both γ2 and the postsynaptic scaffolding protein gephyrin showed diminished total protein levels following a single DZP treatment in vitro and in mouse cortical tissue. We further identified DZP treatment enhanced phosphorylation of gephyrin Ser270 and increased generation of gephyrin cleavage products. Selective immunoprecipitation of γ2 from cultured neurons revealed enhanced ubiquitination of this subunit following DZP exposure. To assess novel trafficking responses induced by DZP, we employed a γ2 subunit containing an N terminal fluorogen-activating peptide (FAP) and pH-sensitive green fluorescent protein (γ2 pH FAP). Live-imaging experiments using γ2 pH FAP GABA A R expressing neurons identified enhanced lysosomal targeting of surface GABA A Rs and increased overall accumulation in vesicular compartments in response to DZP. Using fluorescence resonance energy transfer (FRET) measurements between α2 and γ2 subunits within a GABA A R in neurons, we identified reductions in synaptic clusters of this subpopulation of surface BZD sensitive receptor. Moreover, we found DZP simultaneously enhanced synaptic exchange of both γ2-GABA A Rs and gephyrin using fluorescence recovery after photobleaching (FRAP) techniques. Finally we provide the first proteomic analysis of the BZD sensitive GABA A R interactome in DZP vs. vehicle treated mice. Collectively, our results indicate DZP exposure elicits down-regulation of gephyrin scaffolding and BZD sensitive GABA A R synaptic availability via multiple dynamic trafficking processes.

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“…It has been suggested that the apparent acute tolerance to the actions of diazepam in man is due to redistribution of the compound from the central nervous system to the peripheral tissues (Greenblatt & Shader, 1986). Acute tolerance to the hypnotic e ect of diazepam in mice may not be attributed to changes in pharmacokinetic factors (Yoong et al, 1986).…”

Section: Discussionmentioning

confidence: 99%

Rate of change of blood concentrations is a major determinant of the pharmacodynamics of midazolam in rats

Cleton

Mazee

Voskuyl³

et al. 1999

British J Pharmacology

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1 The objective of this investigation was to characterize quantitatively the in¯uence of the rate of increase in blood concentrations on the pharmacodynamics of midazolam in rats. The pharmacodynamics of midazolam were quanti®ed by an integrated pharmacokinetic-pharmacodynamic modelling approach. 2 Using a computer controlled infusion technique, a linear increase in blood concentrations up to 80 ng ml 71 was obtained over di erent time intervals of 1 ± 6 h, resulting in rates of rise of the blood concentrations of respectively, 1.25, 1.00, 0.87, 0.46, 0.34 and 0.20 ng ml 71 min 71 . In one group of rats the midazolam concentration was immediately brought to 80 ng ml 71 and maintained at that level for 4 h. Immediately after the pretreatment an intravenous bolus dose was given to determine the time course of the EEG e ect in conjunction with the decline of midazolam concentrations. 3 The increase in b activity (11.5 ± 30 Hz) of the EEG was used as pharmacodynamic endpoint. For each individual animal the relationship between blood concentration and the EEG e ect could be described by the sigmoidal E max model. After placebo, the values of the pharmacodynamic parameter estimates were E max =82+5 mV, EC 50,u =6.4+0.8 ng ml 71 and Hill factor=1.4+0.1. A bell-shaped relationship between the rate of change of midazolam concentration and the value of EC 50,u was observed with a maximum of 21+5.0 ng ml 71 at a rate of change of 0.46 ng ml 71 min 71 ; lower values of EC 50,u were observed at both higher and lower rates. 4 The ®ndings of this study show that the rate of change in plasma concentrations is an important determinant of the pharmacodynamics of midazolam in rats.

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Acute Tolerance to Diazepam in Mice: Pharmacokinetic Considerations

Cited by 10 publications

References 12 publications

Pharmacokinetic‐pharmacodynamic modelling of the EEG effects of midazolam in individual rats: influence of rate and route of administration

Pharmacokinetic‐pharmacodynamic modelling of the EEG effects of midazolam in individual rats: influence of rate and route of administration

Diazepam Accelerates GABAAR Synaptic Exchange and Alters Intracellular Trafficking

Rate of change of blood concentrations is a major determinant of the pharmacodynamics of midazolam in rats

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