Effects of non‐sedative anxiolytic drugs on responses to GABA and on diazepam‐induced enhancement of these responses on mouse neurones in cell culture

Deyn, Peter Paul De; Macdonald, Robert L.

doi:10.1111/j.1476-5381.1988.tb16554.x

Cited by 10 publications

(3 citation statements)

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“…Diazepam concentration -response curves were obtained for neurons isolated from control animals ( filled boxes, solid line; n ϭ 9) and for neurons isolated from animals undergoing status epilepticus ( filled circles, dashed line; n ϭ 12). Higher concentrations of diazepam inhibited GABAR current as reported previously (De Deyn and Macdonald, 1988). concentration -dentate granule cell GABAR current reduction relationships.…”

Section: Pentobarbital Enhancement Of Gabar Currentssupporting

confidence: 56%

Rapid Seizure-Induced Reduction of Benzodiazepine and Zn²⁺Sensitivity of Hippocampal Dentate Granule Cell GABA_AReceptors

Kapur¹,

1997

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Fast synaptic inhibition in the forebrain is mediated primarily by GABA acting on GABA A receptors (GABARs). GABARs are regulated by numerous positive (barbiturates, benzodiazepines, and neurosteroids) and negative (picrotoxin, bicuculline, and Zn 2ϩ ) allosteric modulators. The sensitivity of GABARs to GABA and to allosteric modulators changes gradually during normal development, during development of chronic epilepsy, and after prolonged exposure to GABAR agonists. Here we report the development of rapid functional plasticity of GABARs occurring over 45 min of continuous seizures (status epilepticus) in rats. Seizures induced in rats by administration of lithium followed by pilocarpine were readily terminated by the benzodiazepine diazepam when administered early during the seizures (after 10 min of seizures). However, during status epilepticus, there was a substantial reduction of diazepam potency for termination of the seizures. To determine whether the loss of sensitivity of the animals to diazepam was caused by an alteration of GABAR functional properties, we obtained whole-cell GABAR currents from hippocampal dentate granule cells isolated acutely from control rats and from rats undergoing status epilepticus. GABAR properties were characterized by determining GABA sensitivity and the sensitivity of GABARs to regulation by benzodiazepines, barbiturates, and Zn 2ϩ. When compared with those from naive controls, GABAR currents from rats undergoing status epilepticus were less sensitive to diazepam and Zn 2ϩ but retained their sensitivity to GABA and pentobarbital. We conclude that the prolonged seizures of status epilepticus rapidly altered the functional properties of hippocampal dentate granule cell GABARs.

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Section: Pentobarbital Enhancement Of Gabar Currentssupporting

confidence: 56%

Rapid Seizure-Induced Reduction of Benzodiazepine and Zn²⁺Sensitivity of Hippocampal Dentate Granule Cell GABA_AReceptors

Kapur¹,

1997

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“…Spinal cord cells were obtained from albino Swiss mouse foetuses (12 ± 14 days of gestation). Neurones were grown and maintained in vitro as described in detail previously (De Deyn & Macdonald, 1988). Cultures were 4 ± 6 weeks old when used in tight-seal whole-cell recording experiments.…”

Section: Methodsmentioning

confidence: 99%

Selective block of N‐methyl‐d‐aspartic acid (NMDA)‐evoked whole‐cell currents in mouse cultured spinal neurones by CGP 40116

D’Hooge

Raes

Bogaert

et al. 1997

British J Pharmacology

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1 CGP 40116 is the active (R)-enantiomer of the most potent N-methyl-D-aspartic acid (NMDA) receptor antagonist presently available: 2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849). In this study, we describe the e ect of CGP 40116 on whole-cell currents induced by excitatory amino acids in cultured mouse spinal cord cells by use of the whole-cell patch-clamp technique. 2 We found that application of CGP 40116 in the nM range, concentration-dependently inhibited whole-cell current evoked by 20 mM NMDA in mouse cultured spinal neurones (IC 50 +s.e.mean 48+8 nM CGP 40116). 3 The compound appeared to be highly selective for the NMDA current. At concentrations as high 1 mM, currents evoked by a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or kainic acid were not a ected by CGP 40116. The threshold concentration for antagonism of NMDA-induced responses was 10 nM suggesting a selectivity ratio of 5100 fold for NMDA receptors versus AMPA or kainate receptors. 4 CGP 40116 produced a parallel rightward displacement of the NMDA log concentration-current curve indicating competitive antagonism at the transmitter recognition site of the NMDA receptor complex. An apparent dissociation constant for the antagonist was calculated from the displacement of the agonist concentration-current curve: 117+53 nM CGP 40116 (estimated K d +s.e.). Like other competitive NMDA antagonists, CGP 40116 blocked NMDA-evoked current in a voltage-independent manner.

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“…Its mechanism of action is by binding to the benzodiazepine site and acting as full agonist which in turn positively modulates benzodiazepine sensitive GABAA receptors and enhances GABA binding at the GABAA receptors to produce its pharmacological properties. 18,19,20 This study was undertaken to compare the therapeutic efficacy and safety of low dose Doxepin with that of Zopiclone in the treatment of Indian patients with primary insomnia to test the assumption that Doxepin would be equally effective, safe and well tolerated in comparison to Zopiclone.…”

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confidence: 99%

A Double Blind, Randomized, Parallel Group, Prospective, Clinical Study for Evaluation of Efficacy and Safety of Low Dose Doxepin in Comparision With Zopiclone in Adult and Elderly Patients With Primary Insomnia

Rastogi¹,

Rastogi²

2015

jemds

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BACKGROUND:Insomnia is underappreciated public health issue. In recent years, insomnia treatment has advanced beyond the routine use of benzodiazepines. AIMS: To compare the efficacy and safety of low dose Doxepin with Zopiclone in patients with primary insomnia. SETTINGS AND DESIGN: A double blind, randomized parallel group, prospective study of low dose Doxepin (n=20) and Zopiclone (n=15) in patients with primary insomnia. METHODS & MATERIAL:Patients fulfilling the selection criteria were enrolled. Enrolled patients were randomized to 2 groups-of low dose Doxepin(3mg) and Zopiclone (3.75mg). Patients were provided with sleep diaries to record sleep parameters, change in alertness and mood, sleepiness scale score and other adverse events were recorded. STATISTICAL ANALYSIS: Student 't' test. RESULTS: Both the groups show significant reduction the time of wakening after sleep onset, with improvement in both total sleep time & sleep efficiency. Both the drugs were well tolerated and percentage change in mood and alertness was comparable. CONCLUSION: Low dose Doxepin was found to be as effective and safe as Zopiclone in patients of primary insomnia. HOW TO CITE THIS ARTICLE:

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Effects of non‐sedative anxiolytic drugs on responses to GABA and on diazepam‐induced enhancement of these responses on mouse neurones in cell culture

Cited by 10 publications

References 54 publications

Rapid Seizure-Induced Reduction of Benzodiazepine and Zn²⁺Sensitivity of Hippocampal Dentate Granule Cell GABA_AReceptors

Rapid Seizure-Induced Reduction of Benzodiazepine and Zn²⁺Sensitivity of Hippocampal Dentate Granule Cell GABA_AReceptors

Selective block of N‐methyl‐d‐aspartic acid (NMDA)‐evoked whole‐cell currents in mouse cultured spinal neurones by CGP 40116

A Double Blind, Randomized, Parallel Group, Prospective, Clinical Study for Evaluation of Efficacy and Safety of Low Dose Doxepin in Comparision With Zopiclone in Adult and Elderly Patients With Primary Insomnia

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Effects of non‐sedative anxiolytic drugs on responses to GABA and on diazepam‐induced enhancement of these responses on mouse neurones in cell culture

Cited by 10 publications

References 54 publications

Rapid Seizure-Induced Reduction of Benzodiazepine and Zn2+Sensitivity of Hippocampal Dentate Granule Cell GABAAReceptors

Rapid Seizure-Induced Reduction of Benzodiazepine and Zn2+Sensitivity of Hippocampal Dentate Granule Cell GABAAReceptors

Selective block of N‐methyl‐d‐aspartic acid (NMDA)‐evoked whole‐cell currents in mouse cultured spinal neurones by CGP 40116

A Double Blind, Randomized, Parallel Group, Prospective, Clinical Study for Evaluation of Efficacy and Safety of Low Dose Doxepin in Comparision With Zopiclone in Adult and Elderly Patients With Primary Insomnia

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Rapid Seizure-Induced Reduction of Benzodiazepine and Zn²⁺Sensitivity of Hippocampal Dentate Granule Cell GABA_AReceptors

Rapid Seizure-Induced Reduction of Benzodiazepine and Zn²⁺Sensitivity of Hippocampal Dentate Granule Cell GABA_AReceptors