2. Academic Validation
  3. 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

  • Sci Rep. 2017 Jun 14;7(1):3503. doi: 10.1038/s41598-017-03154-5.
Monika Balk 1 2,  Harald Hentschke 1,  Uwe Rudolph 3 4,  Bernd Antkowiak 1 5,  Berthold Drexler 6
Affiliations

Affiliations

  • 1 Department of Anaesthesiology, Experimental Anaesthesiology Section, Eberhard-Karls-University, Waldhörnlestrasse 22, 72072, Tübingen, Germany.
  • 2 Department of Anaesthesiology and Intensive Care Medicine, Esslingen Hospital, Hirschlandstr. 97, 73730, Esslingen, Germany.
  • 3 Laboratory of Genetic Neuropharmacology, McLean Hospital and Department of Psychiatry, Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, USA.
  • 4 Department of Psychiatry, Harvard Medical School, 401 Park Drive, Boston, MA, 02215, USA.
  • 5 Werner Reichardt Centre for Integrative Neuroscience, Eberhard-Karls-University, Otfried-Müller-Str. 25, 72076, Tübingen, Germany.
  • 6 Department of Anaesthesiology, Experimental Anaesthesiology Section, Eberhard-Karls-University, Waldhörnlestrasse 22, 72072, Tübingen, Germany. [email protected].
PMID: 28615640 DOI: 10.1038/s41598-017-03154-5
Abstract

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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