Diazepam Decreases Action Potential Firing of Neocortical Neurons via Two Distinct Mechanisms

Drexler, Berthold; Zinser, Stefan; Hentschke, Harald; Antkowiak, Bernd

doi:10.1213/ane.0b013e3181f9c035

Cited by 37 publications

(38 citation statements)

References 25 publications

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“…This is in close agreement with results obtained from previous studies with diazepam 11, 14 . The most convincing hypothesis to explain this biphasic depression is the existence of at least two benzodiazepine binding sites, as proposed by Walters et al ., leading to two separate mechanisms of benzodiazepine action 14 .…”

Section: Discussionsupporting

confidence: 93%

“…There are, however, several possibilities to explain this finding: First, a saturation at the classical benzodiazepine site 11 and second, a novel binding site for benzodiazepines at the GABA A receptor, preventing further depression, as suggested in a previous study by Baur et al . 20 .…”

Section: Discussionmentioning

confidence: 90%

“…Moreover, it was suggested that sedation with diazepam depends on GABA A receptors located on glutamatergic neurons in the cerebral cortex 10 . On the cellular level, this molecular action of diazepam translates into a significant depression of cortical network action potential firing 11 . Therefore, in order to examine the contribution of α1-containing GABA A receptors to this phenomenon, in the current study clinically relevant concentrations of midazolam were also tested in neocortical slice cultures from GABA A receptor α 1 (H101R) knock-in mice.…”

Section: Introductionmentioning

confidence: 99%

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Differential depression of neuronal network activity by midazolam and its main metabolite 1-hydroxymidazolam in cultured neocortical slices

Balk

Hentschke

Rudolph

et al. 2017

Sci Rep

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The benzodiazepine midazolam is widely used in critical care medicine. Midazolam has a clinically active metabolite, 1-hydroxymidazolam. The contribution of 1-hydroxymidazolam to the effects of midazolam is controversial. The aim of the current study was to compare the actions of midazolam and 1-hydroxymidazolam on network activity of cortical neurons. Midazolam depressed neuronal activity at a low concentration of 5 nM. When midazolam concentration was increased, it depressed neuronal discharge rates in a biphasic manner. In comparison, 1-hydroxymidazolam did not depress the cortical network activity at low nanomolar concentrations. Higher concentrations of 1-hydroxymidazolam consistently inhibited neuronal activity. Moreover, midazolam shortened cortical up states at low, but not at high concentrations, while the opposite effect was observed with 1-hydroxymidazolam. The network depressant action of midazolam at low concentrations was absent in slices from GABAA receptor α1(H101R)mutant mice. The α1(H101R)mutation renders α1-subunit containing GABAA receptors insensitive towards benzodiazepines. This GABAA receptor subtype is thought to mediate sedation. As midazolam is more potent than its metabolite 1-hydroxymidazolam, the major clinical effects are thus likely caused by midazolam itself. However, 1-hydroxymidazolam could add to the effects of midazolam, especially after the application of high doses of midazolam, and in case of impaired drug metabolism.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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Differential depression of neuronal network activity by midazolam and its main metabolite 1-hydroxymidazolam in cultured neocortical slices

Balk

Hentschke

Rudolph

et al. 2017

Sci Rep

Self Cite

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“…In accordance with these findings in rodents, functional magnetic resonance imaging studies showed that sedative drugs reduce blood flow predominantly in neocortical circuits of human subjects (Heinke and Koelsch, 2005). On the cellular level, benzodiazepines significantly depress action potential activity of neocortical neurons (Drexler et al, 2010), supporting the idea that this action is causally linked to sedation. Neocortical neurons express a great diversity of GABA A receptor-subtypes (Fritschy and Brünig, 2003).…”

Section: Introductionmentioning

confidence: 70%

Enhancing the function of alpha5-subunit-containing GABAA receptors promotes action potential firing of neocortical neurons during up-states

Drexler

Zinser

Huang

et al. 2013

European Journal of Pharmacology

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Neocortical neurons mediate the sedative and anticonvulsant properties of benzodiazepines. These agents enhance synaptic inhibition via positive modulation of -aminobutyric acid (GABAA) receptors harbouring 1-, 2-, 3- or 5-protein subunits. Benzodiazepine-sensitive GABAA receptors containing the 5-subunit are abundant in the neocortex, but their impact in controlling neuronal firing patterns is unknown. Here we studied how the discharge rates of cortical neurons are modified by a positive (SH-053-2′F-R-CH3) and a negative (L 655,708) 5-subunit-preferring allosteric modulator in comparison to diazepam, the classical non-selective benzodiazepine. Drug actions were characterized in slice cultures from wild-type and 5(H105R) knock-in mice by performing extracellular multi-unit-recordings. In knock-in mice, receptors containing the 5 subunit are insensitive to benzodiazepines. The non-selective positive allosteric modulator diazepam decreased the discharge rates of neocortical neurons during episodes of ongoing neuronal activity (up states). In contrast to diazepam, the 5-preferring positive modulator SH-053-2′F-R-CH3 accelerated action potential firing during up states. This promoting action was absent in slices from 5(H105R) mice, confirming that it is mediated by the 5-subunit. Consistent with these observations, the negative 5-selective modulator L 655,708 inhibited up state action potential activity in slices from wild-type mice. The opposing actions of diazepam and SH-053-2′F-R-CH3, which both enhance GABAA receptor function but differ in subtype-selectivity, uncovers contrasting roles of GABAA receptor subtypes in controlling the firing rates of cortical neurons. These findings may have important implications for the design of novel anaesthetic and anticonvulsant benzodiazepines displaying an improved efficacy and fewer side effects.

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“…Furthermore, anesthetic agents depress action potential firing and oscillatory network activity in neocortical brain slices (Lukatch et al 2005) and organotypic cultures (Antkowiak and Helfrich-Forster 1998). Similar effects were seen with benzodiazepines (Drexler et al 2010) and barbiturates (Lukatch and MacIver 1996) which are used clinically to induce sedation. To date, brain slice assays have not been utilized in the assessment of potential sedative effects, and this is unlikely to be used as a routine screen in preclinical safety assessment.…”

Section: In Vitro Sleep And/or Sedation Assessmentmentioning

confidence: 78%

CNS Adverse Effects: From Functional Observation Battery/Irwin Tests to Electrophysiology

Fonck

Easter

Pietras

et al. 2015

Principles of Safety Pharmacology

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This chapter describes various approaches for the preclinical assessment of drug-induced central nervous system (CNS) adverse effects. Traditionally, methods to evaluate CNS effects have consisted of observing and scoring behavioral responses of animals after drug is administered. Among several behavioral testing paradigms, the Irwin and the functional observational battery (FOB) are the most commonly used assays for the assessment of CNS effects. The Irwin and FOB are considered good first-tier assays to satisfy the ICH S7A guidance for the preclinical evaluation of new chemical entities (NCE) intended for humans. However, experts have expressed concern about the subjectivity and lack of quantitation that is derived from behavioral testing. More importantly, it is difficult to gain insight into potential mechanisms of toxicity by assessing behavioral outcomes. As a complement to behavioral testing, we propose using electrophysiology-based assays, both in vivo and in vitro, such as electroencephalograms and brain slice field-potential recordings. To better illustrate these approaches, we discuss the implementation of electrophysiology-based techniques in drug-induced assessment of seizure risk, sleep disruption, and cognitive impairment.

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Diazepam Decreases Action Potential Firing of Neocortical Neurons via Two Distinct Mechanisms

Cited by 37 publications

References 25 publications

Differential depression of neuronal network activity by midazolam and its main metabolite 1-hydroxymidazolam in cultured neocortical slices

Differential depression of neuronal network activity by midazolam and its main metabolite 1-hydroxymidazolam in cultured neocortical slices

Enhancing the function of alpha5-subunit-containing GABAA receptors promotes action potential firing of neocortical neurons during up-states

CNS Adverse Effects: From Functional Observation Battery/Irwin Tests to Electrophysiology

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