Valium without dependence? Individual GABA_A receptor subtype contribution toward benzodiazepine addiction, tolerance, and therapeutic effects

Abstract

Benzodiazepines are one of the most prescribed medications as first-line treatment of anxiety, insomnia, and epilepsy around the world. Over the past two decades, advances in the neuropharmacological understanding of gamma aminobutyric acid (GABA)A receptors revealed distinct contributions from each subtype and produced effects. Recent findings have highlighted the importance of α1 containing GABAA receptors in the mechanisms of addiction and tolerance in benzodiazepine treatments. This has shown promise in the development of tranquilizers with minimal side effects such as cognitive impairment, dependence, and tolerance. A valium-like drug without its side effects, as repeatedly demonstrated in animals, is achievable.

Detoxification Improves Multidomain Cognitive Dysfunction in High-Dose Benzodiazepine Abusers

“…Animal models indicate that prolonged α 1 stimulation induces a shift in the expression of α isoforms, causing reduction of α 1 , α 2 , increase of α 3 , α 4 and α 6 , and reduction or increase in α 5 subunits (Tan et al, 2011). α 4 and α 6 subunits are nearly insensitive to BZDs, and the changes in the composition of the GABA-A receptor result in BZD-receptor decoupling, a compensatory mechanism that contributes to BZD tolerance (Cheng et al, 2018). While tolerance to sedative and anticonvulsant effects builds quickly in humans and animal models, cognitive effects of BZDs seem to lack tolerance (Cheng et al, 2018).…”

“…α 4 and α 6 subunits are nearly insensitive to BZDs, and the changes in the composition of the GABA-A receptor result in BZD-receptor decoupling, a compensatory mechanism that contributes to BZD tolerance (Cheng et al, 2018). While tolerance to sedative and anticonvulsant effects builds quickly in humans and animal models, cognitive effects of BZDs seem to lack tolerance (Cheng et al, 2018).…”

Looking for Novelty in an “Old” Receptor: Recent Advances Toward Our Understanding of GABAARs and Their Implications in Receptor Pharmacology

“…As a result of the predominant behavioral effects produced by α1- and α2-containing GABA A Rs, there have been attempts to develop novel compounds that target these GABA A R subtypes specifically. Most notably, non-benzodiazepines (also known as z-drugs) were developed and are used as sleep aids due to their higher selectivity for α1-containing GABA A Rs ( Atack, 2011 ; Tan et al, 2011 ; Cheng et al, 2018 ; Sieghart and Savić, 2018 ). However, there are currently no FDA-approved, subtype-selective GABA A R-targeting drugs that function as anxiolytics and are devoid of sedative properties.…”

Benzodiazepines: Dependence and addiction in general practice

“…Tolerance is often explained as a homeostatic process through receptor downregulation in the presence of a constant stimulus. However, this does not appear to be the mechanism with benzodiazepines, which appears multifactorial (Cheng et al., 2018).…”

“…An increased tolerance means larger quantities are required to establish the effects of previous, lower doses. Tolerance to benzodiazepines is poorly understood; it develops quickly to hypnotic and anticonvulsant effects, but not with their anxiolytic and amnesic effects, particularly when used intermittently and over long periods (Baldwin et al, 2013;Cheng et al, 2018;Vinkers and Olivier, 2012). Tolerance is often explained as a homeostatic process through receptor downregulation in the presence of a constant stimulus.…”