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 different subunits of the GABA(A) receptor (GABA(A)R) with three - (1, 2 and 5) and two - (1, 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--carboline-3-carboxylate (DMCM) in TMN neurons using mouse genetics, electrophysiological and molecular biological methods. Key Results We find the sensitivity of GABA(A)R to zolpidem, midazolam and DMCM significantly reduced in TMN neurons from 2F77I mice, but modulatory activities of diazepam, chlordiazepoxide and flumazenil not affected. Potencies and efficacies of these compounds are in line with the dominance of 2- and 1-subunit containing receptors associated with 2- or 1-subunits. Functional expression of the 1-subunit is supported by siRNA-based knock-down experiments in 2F77I mice. Conclusions and Implications GABA(A)R of TMN neurons respond to a variety of common sedatives with a high affinity binding site (2F77I) involved. The 1-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.