Bottom-Up versus Top-Down Induction of Sleep by Zolpidem Acting on Histaminergic and Neocortex Neurons

Zolpidem, a GABAA receptor-positive modulator, is the gold-standard drug for treating insomnia. Zolpidem prolongs IPSCs to decrease sleep latency and increase sleep time, effects that depend on α2 and/or α3 subunit-containing receptors. Compared with natural NREM sleep, zolpidem also decreases the EEG power, an effect that depends on α1 subunit-containing receptors, and which may make zolpidem-induced sleep less optimal. In this paper, we investigate whether zolpidem needs to potentiate only particular GABAergic pathways to induce sleep without reducing EEG power. Mice with a knock-in F77I mutation in the GABAA receptor γ2 subunit gene are zolpidem-insensitive. Using these mice, GABAA receptors in the frontal motor neocortex and hypothalamic (tuberomammillary nucleus) histaminergic-neurons of γ2I77 mice were made selectively sensitive to zolpidem by genetically swapping the γ2I77 subunits with γ2F77 subunits. When histamine neurons were made selectively zolpidem-sensitive, systemic administration of zolpidem shortened sleep latency and increased sleep time. But in contrast to the effect of zolpidem on wild-type mice, the power in the EEG spectra of NREM sleep was not decreased, suggesting that these EEG power-reducing effects of zolpidem do not depend on reduced histamine release. Selective potentiation of GABAA receptors in the frontal cortex by systemic zolpidem administration also reduced sleep latency, but less so than for histamine neurons. These results could help with the design of new sedatives that induce a more natural sleep

A call for the appropriate application of clinical pharmacological principles in the search for safe and efficacious COVID-19 (SARS-COV-2) treatments.

Syndrome Coronavirus 2 (SARS-CoV-2) has led to remarkable efforts by the scientific communities internationally to identify potential pharmacological treatments through the rapid initiation of clinical trials of novel and/or re-purposed regulatory authorityapproved therapies. We greatly welcome the significant global effort to safely expedite trials. However, we are concerned that many studies have not been of high quality to generate clinically meaningful data to enable effective translation to clinical practice. Identifying the “right” drug (or drug combinations) is only the first step. Applying core clinical pharmacology principles at all stages of research will help identify the right dose, the right patient, and the right treatment protocol. We hope that by setting out the principles outlined in this statement, efforts to find a safe and efficacious treatment for COVID-19 will have the best chance of success

GABA Receptors and the Pharmacology of Sleep

Current GABAergic sleep-promoting medications were developed pragmatically, without making use of the immense diversity of GABAA receptors. Pharmacogenetic experiments are leading to an understanding of the circuit mechanisms in the hypothalamus by which zolpidem and similar compounds induce sleep at α2βγ2-type GABAA receptors. Drugs acting at more selective receptor types, for example, at receptors containing the α2 and/or α3 subunits expressed in hypothalamic and brain stem areas, could in principle be useful as hypnotics/anxiolytics. A highly promising sleep-promoting drug, gaboxadol, which activates αβδ-type receptors failed in clinical trials. Thus, for the time being, drugs such as zolpidem, which work as positive allosteric modulators at GABAA receptors, continue to be some of the most effective compounds to treat primary insomnia

An Evaluation of the Integrative Pharmacology Fund: Lessons for the future of in vivo education and training

This is the final version of the article. Available from British Pharmacological Society via the link in this record.n/aBritish Pharmacological Societ

Robust photoregulation of GABAA receptors by allosteric modulation with a propofol analogue

Photochemical switches represent a powerful method for improving pharmacological therapies and controlling cellular physiology. Here we report the photo-regulation of GABA(A) receptors (GABA(A)Rs) by a derivative of propofol (2,6-diisopropylphenol), a GABA(A)R allosteric modulator, that we have modified to contain photo-isomerizable azobenzene. Using α(1)β(2)γ(2) GABA(A)Rs expressed in Xenopus laevis oocytes and native GABA(A)Rs of isolated retinal ganglion cells, we show that the trans-azobenzene isomer of the new compound (trans-MPC088), generated by visible light (wavelengths ~440 nm), potentiates the GABA-elicited response and at higher concentrations directly activates the receptors. cis-MPC088, generated from trans-MPC088 by UV light (~365 nm), produces little if any receptor potentiation/activation. In cerebellar slices, MPC088 co-applied with GABA affords bidirectional photo-modulation of Purkinje cell membrane current and spike-firing rate. The findings demonstrate photo-control of GABA(A)Rs by an allosteric ligand and open new avenues for fundamental and clinically oriented research on GABA(A)Rs, a major class of neurotransmitter receptors in the central nervous system