GABAA receptor subtypes and benzodiazepine use, misuse, and abuse

Abstract

Benzodiazepines have been in use for over half a century. While they remain highly prescribed, their unfavorable side-effect profile and abuse liability motivated a search for alternatives. Most of these efforts focused on the development of benzodiazepine-like drugs that are selective for specific GABAA receptor subtypes. While there is ample evidence that subtype-selective GABAA receptor ligands have great potential for providing symptom relief without typical benzodiazepine side-effects, it is less clear whether subtype-selective targeting strategies can also reduce misuse and abuse potential. This review focuses on the three benzodiazepine properties that are relevant to the DSM-5-TR criteria for Sedative, Hypnotic, or Anxiolytic Use Disorder, namely, reinforcing properties of benzodiazepines, maladaptive behaviors related to benzodiazepine use, and benzodiazepine tolerance and dependence. We review existing evidence regarding the involvement of different GABAA receptor subtypes in each of these areas. The reviewed studies suggest that α1-containing GABAA receptors play an integral role in benzodiazepine-induced plasticity in reward-related brain areas and might be involved in the development of tolerance and dependence to benzodiazepines. However, a systematic comparison of the contributions of all benzodiazepine-sensitive GABAA receptors to these processes, a mechanistic understanding of how the positive modulation of each receptor subtype might contribute to the brain mechanisms underlying each of these processes, and a definitive answer to the question of whether specific chronic modulation of any given subtype would result in some or all of the benzodiazepine effects are currently lacking from the literature. Moreover, how non-selective benzodiazepines might lead to the maladaptive behaviors listed in DSM and how different GABAA receptor subtypes might be involved in the development of these behaviors remains unexplored. Considering the increasing burden of benzodiazepine abuse, the common practice of benzodiazepine misuse that leads to severe dependence, and the current efforts to generate side-effect free benzodiazepine alternatives, there is an urgent need for systematic, mechanistic research that provides a better understanding of the brain mechanisms of benzodiazepine misuse and abuse, including the involvement of specific GABAA receptor subtypes in these processes, to establish an informed foundation for preclinical and clinical efforts.

Long-term use of benzodiazepines in chronic insomnia: a European perspective

“…Although the primary sites of action of BZDs are the GABA receptor subunits, they also indirectly enhance dopamine release in the nucleus accumbens ( 68 ). This increase in dopamine concentration is responsible for the addictive properties of BZDs and ZDs ( 69 , 70 ).…”

Relationship between clock gene expression and CYP2C19 and CYP3A4 with benzodiazepines

“…16,17 Benzodiazepine abuse and dependence are also global problems and are responsible for the majority of fatal overdose cases. 18,19 On the other hand, drug-metabolizing enzymes such as CYP3A4 and CYP2C19, are mainly involved in BZD metabolism. 9,10 Since clock genes are involved in CYP regulation, it is expected that the extent of side effects will differ according to the time of drug intake.…”

Established and emerging GABAA receptor pharmacotherapy for epilepsy

“…Clobazam is a 1,5-benzodiazepine and possesses a different molecular structure to classical 1,4- benzodiazepines such as diazepam. This confers greater selectivity to GABA A receptors possessing the α2 subunit which may be implicated in the anticonvulsant effects of BZDs, and is associated with other favourable properties such as improved tolerability ( Stephens et al, 2017 ; Engin, 2022 ). Consequently, clobazam has a more established role in the long-term management of epilepsy, with robust evidence in the treatment of the DEE Lennox-Gastaut Syndrome.…”