Benzodiazepine‐site pharmacology on GABAA receptors in histaminergic neurons

Background and Purpose The histaminergic tuberomamillary nucleus (TMN) of the posterior hypothalamus controls the cognitive aspects of vigilance which is reduced by common sedatives and anxiolytics. The receptors targeted by these drugs in histaminergic neurons are unknown. TMN neurons express nine...

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Bibliographic Details
Published in:British journal of pharmacology 2013-09, Vol.170 (1), p.222-232
Main Authors: May, A C, Fleischer, W, Kletke, O, Haas, H L, Sergeeva, O A
Format: Article
Language:English
Subjects:
Animals
Benzodiazepines - pharmacology
Binding Sites
GABA
GABA Modulators - pharmacology
Gene Knockdown Techniques
histamine
Histamine - metabolism
Hypnotics and Sedatives - pharmacology
Hypothalamus, Posterior - drug effects
Hypothalamus, Posterior - metabolism
Male
Mice
Mice, Mutant Strains
microelectrode array
Neurons
Neurons - drug effects
Neurons - metabolism
Protein Subunits
Receptors, GABA-A - drug effects
Receptors, GABA-A - metabolism
RNA, Small Interfering - administration & dosage
single‐cell RT‐PCR
Themed Issue: Histamine Pharmacology Update
whole‐cell patch‐clamp
zolpidem
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Summary:Background and Purpose The histaminergic tuberomamillary nucleus (TMN) of the posterior hypothalamus controls the cognitive aspects of vigilance which is reduced by common sedatives and anxiolytics. The receptors targeted by these drugs in histaminergic neurons are unknown. TMN neurons express nine different subunits of the GABAA receptor (GABAAR) with three α‐ (α1, α2 and α5) and two γ‐ (γ1, γ 2) subunits, which confer different pharmacologies of the benzodiazepine‐binding site. Experimental Approach We investigated the actions of zolpidem, midazolam, diazepam, chlordiazepoxide, flumazenil (Ro15‐1788) and methyl‐6,7‐dimethoxy‐4‐ethyl‐β‐carboline‐3‐carboxylate (DMCM) in TMN neurons using mouse genetics, electrophysiological and molecular biological methods. Key Results We find the sensitivity of GABAAR to zolpidem, midazolam and DMCM significantly reduced in TMN neurons from γ2F77I mice, but modulatory activities of diazepam, chlordiazepoxide and flumazenil not affected. Potencies and efficacies of these compounds are in line with the dominance of α2‐ and α1‐subunit containing receptors associated with γ2‐ or γ1‐subunits. Functional expression of the γ1‐subunit is supported by siRNA‐based knock‐down experiments in γ2F77I mice. Conclusions and Implications GABAAR of TMN neurons respond to a variety of common sedatives with a high affinity binding site (γ2F77I) involved. The γ1‐subunit likely contributes to the action of common sedatives in TMN neurons. This study is relevant for understanding the role of neuronal histamine and benzodiazepines in disorders of sleep and metabolism. Linked Articles This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/ 10.1111/bph.2013.170.issue‐1
ISSN:0007-1188
1476-5381
DOI:10.1111/bph.12280