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Individual GABA Receptor Subtype Contribution Toward Benzodiazepine Journal name: Neuropsychiatric Disease and Treatment Article Designation: Review Year: 2018 Volume: 14 Neuropsychiatric Disease and Treatment Dovepress Running head verso: Cheng et al Running head recto: Individual GABAA receptor contribution to benzodiazepine effects open access to scientific and medical research DOI: 164307 Open Access Full Text Article REVIEW Valium without dependence? Individual GABAA receptor subtype contribution toward benzodiazepine addiction, tolerance, and therapeutic effects Tianze Cheng1 Abstract: Benzodiazepines are one of the most prescribed medications as first-line treatment Dominique Marie Wallace2 of anxiety, insomnia, and epilepsy around the world. Over the past two decades, advances in the 1 neuropharmacological understanding of gamma aminobutyric acid (GABA) receptors revealed Benjamin Ponteri A Mahir Tuli3 distinct contributions from each subtype and produced effects. Recent findings have highlighted the importance of α containing GABA receptors in the mechanisms of addiction and tolerance 1Pitzer College, Claremont, CA, USA; 1 A 2Portland State University, Portland, in benzodiazepine treatments. This has shown promise in the development of tranquilizers with OR, USA; 3University of British minimal side effects such as cognitive impairment, dependence, and tolerance. A valium-like For personal use only. Columbia, Vancouver, BC, Canada drug without its side effects, as repeatedly demonstrated in animals, is achievable. Keywords: benzodiazepines, subtype, tolerance, dependence, anxiolytic, GABAA receptor Introduction Benzodiazepines are a class of tranquilizers that enhance gamma aminobutyric acid (GABA)ergic transmission. They are seen ubiquitously in the modern health care system as .5% of the total adults in USA are prescribed benzodiazepines each year.1 The major behavioral and psychoactive effects of benzodiazepines include anticon- vulsive, sedative, muscle relaxant, and anxiolytic effects.2 They are readily prescribed by physicians and are regarded as a frontline treatment for many common psychiatric disorders such as anxiety, obsessive-compulsive disorder, seizures, as well as a number of sleep disorders.3 Neuropsychiatric Disease and Treatment downloaded from https://www.dovepress.com/ by 54.70.40.11 on 28-Dec-2018 Benzodiazepines were discovered in 1955 by chemist Leo Sternbach and, when first introduced, were proposed as a promising replacement for barbiturates, another similar class of tranquilizers that also act on GABA.4,5 The medical use of barbiturates was prominent until the 1950s when serious side effects, such as high incidence of abuse, dependence, and overdose finally started to surface.6 When benzodiazepines hit the market in the 1960s, they were thought to be the successor to barbiturates due to lower toxicity and side effects. Despite having a lower abuse profile, benzodiazepines still cause dependence after repeated use, which was not widely recognized until the 1980s.7,8 Correspondence: Tianze Cheng 221-10, 59th Avenue, Flushing, Many attempts to produce dependence and tolerance-free benzodiazepine drugs NY 11364, USA have been investigated in the past. The selective agonist zolpidem was marketed, Tel +1 646 897 1322 Email [email protected] as promising data showed reduced abuse potential.9 However, these results did not submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2018:14 1351–1361 1351 Dovepress © 2018 Cheng et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/NDT.S164307 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Powered by TCPDF (www.tcpdf.org) 1 / 1 Cheng et al Dovepress translate in the clinic since zolpidem causes dependence &KORULGHLRQ FKDQQHO 2WKHUV after repeated use.10 %HQ]RGLD]HSLQH ELQGLQJVLWH α Studies have also attempted to investigate neurophar- α β γ β α α macological mechanisms of benzodiazepines. At first, the α *$%$$ benzodiazepine site was categorized into benzodiazepine UHFHSWRU subtype I and benzodiazepine subtype II, where traditional benzodiazepines bind to both, but triazolopyridazines (TPZs) α have high affinity for only type I.11 It was later found that TPZ Figure 1 The GABAA receptor and its approximate subtype composition (adapted was actually just a selective agonist for one of many subtypes from Wafford’s study). 12 Note: Data from Wafford.19 that exist within the GABAA receptor family. Abbreviation: GABA, gamma aminobutyric acid. Progress in neuropharmacology has revealed various subtypes within the GABAA receptor family, as well as We know that the α1 subtype plays a major role in sedation anatomical and pharmacological differences between them. because α1(H101R) point mutated mice were resilient to Investigations have also been directed toward the addiction sedative effects of benzodiazepines.21 Benzodiazepines that and tolerance mechanisms of benzodiazepines; their rela- possess sparing efficacy atα 1 subtype such as L-838,417 act 21,22 tionships with specific subtypes within the GABAA receptor as a sedation-free anxiolytic in animal models. L-838,417 family will be discussed in further depth. has seen popular use in research and is a partial agonist of α2, 22 α3, and α5 containing GABAA receptors. Other compounds Pharmacological targets of with low or absent α1 subtype efficacy such as imidazenil, benzodiazepine TPA123, and TPA023, are also shown to be sedation-free Benzodiazepines, although referred to as a positive allosteric anxiolytics, revealing the importance of the α1 subtype in 23,24 modulator (PAM) of the GABAA receptor, does not actually the mediation of sedation. enhance GABA’s binding to the receptor, like conventional Moreover, α subtype selective agonists such as zolpidem For personal use only. 1 PAMs. Benzodiazepines increase the frequency of chloride are unable to produce anxiolytic effects other than sedation.25 channel influx which hyperpolarizes the GABA receptor, The α5 inverse agonist, α5IA, improves memory without resulting in increased inhibitory postsynaptic potential.13,14 producing anxiety, increased awakeness, or proconvulsant 26 α1–6, β1–3, γ1–3, δ, ε, θ, and π make up the currently defined effects in animals. So far, we could conclude that anxiety is 15 GABAA subunits in the human brain. Classic benzodiaz- mediated by either α2 or α3 subtypes or both, while sedation epines such as diazepam binds to α1, α2, α3, and α5 containing is mediated by α1 containing GABAA receptors. 16 GABAA receptors. α1 containing GABAA receptors are Because α5IA reversed alcohol-induced memory deficit the most abundant subtype and can be found throughout when given prior to alcohol administration in humans, α5 sub- 26 the brain, while α2, α3, and α5 subtypes are more region type is thought to contribute toward amnesic effects. This 17 specific. was further confirmed when theα 5 subtype was found to be Although numerous combinations exist, most GABAA responsible for amnestic effects of GABAA receptor PAM Neuropsychiatric Disease and Treatment downloaded from https://www.dovepress.com/ by 54.70.40.11 on 28-Dec-2018 receptors structurally contain two α, two β, and a single etomidate, which correspond with earlier studies on the role γ subunit surrounding a chloride ion channel as shown in of the α5 subtype in memory and its anatomical presence in Figure 1.18 The benzodiazepine site is located between the the hippocampus.27 α and γ subunit. However, it seems α5 is not the sole subtype that con- tributes to amnesic effects. α1 subtype full agonist zolpidem Roles of GABAA receptor α1, α2, α3, seemed to produce more memory and cognitive impairment and α5 subunits in benzodiazepine compared to an equivalent dose of triazolam, an agonist of all pharmacology benzodiazepine sites.28 Given that zolpidem produces almost GABAA subtype selective compounds and rodent models no efficacy at theα 5 subtype, we can conclude that α1 subtype of subunit point mutation have provided promising data for is also involved in amnesic effects of benzodiazepines.28 identifying different subunit contributions toward each clini- In 2000, it was thought that α2 subtype solely mediated cal effect. We will discuss clinical effects of sedation first, anxiolytic actions because only α2(H101R) point mutated as it impairs the cognitive performance of benzodiazepine- mice were still anxious after diazepam treatment.29 On the prescribed patients.20 contrary, two studies 5 years later, the first study using 1352 submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2018:14 Dovepress Powered by TCPDF (www.tcpdf.org) 1 / 1 Dovepress Individual GABAA receptor contribution to benzodiazepine effects TP003, an α3 subtype selective agonist, demonstrated that Most anticonvulsive actions of benzodiazepines are 30 TP003 produced strong anxiolytic effects. The second mediated by α1 as diazepam only mildly attenuated penty- study used an α3 subtype inverse agonist α3IA to produce lenetetrazol-induced seizures in α1(H101R) mice. However, anxiogenic effects
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