Author/Editor		Methuku, K. R.; Li, X.; Černe, Rok; Gleason, Scott D.; Schkeryantz, J. M.; Tiruveedhula, V. V. N. P. B.; Golani, L. K.; Li, G.; Poe, M. M.; Witkin, Jeffrey M.
Title		An antidepressant-related pharmacological signature for positive allosteric modulators of [alpha]2/3-containing GABAA receptors
Type		članek
Vol. and No.		, št. Vol. 170
Publication year		2018
Volume		str. 9-13
ISSN		1873-5177 - Pharmacology, biochemistry, and behavior
Language		eng
Abstract		Data from transgenic animals and novel pharmacological agents has realigned scientific scrutiny on the therapeutic potential of positive allosteric modulators (PAMs) of [alpha]2/3-containing GABAA receptors. Evidence for analgesic, anticonvulsant, and anxiolytic activity of [alpha]2/3-selective PAMs has been presented along with the clinical potential for a milder motor-impacting profile compared to non-selective GABAA receptor PAMs. A new series of [alpha]2/3-selective PAMs was recently introduced which has anxiolytic and anticonvulsant activity in rodent models. These molecules also produce efficacy against pain in multiple animal models. Additionally, co-morbid states of depression are prevalent among patients with pain and patients with anxiety. Compounds were shown to be selective for [alpha]2 and [alpha]3 constructs over [alpha]1 (except KRM-II-82), [alpha]4, [alpha]5, and [alpha]6 proteins in electrophysiological assays in transfected HEK-293T cells. Utilizing the forced-swim assay in mice that detects conventional and novel antidepressant drugs, we demonstrate for the first time that [alpha]2/3-selective PAMs are active in the forced-swim assay at anxiolytic-producing doses. In contrast, activity in a related model, the tail-suspension test, was not observed. Diazepam was not active in the forced-swim assay when given alone but produced an antidepressant-like effect in mice when given in conjunction with the [alpha]1-preferring antagonist, -CCT, that attenuated the motor-impairing effects of diazepam. We conclude that these [alpha]2/3-selective PAMs deserve further scrutiny for their potential treatment of major depressive disorder. If effective, such a mechanism could add a beneficial antidepressant component to the anxiolytic, analgesic, and anticonvulsant spectrum of effects of these compounds.
Keywords		depression GABA-A receptors anxiety depresija GABA-A receptorji anksioznost