Review, Jan/2023: GABAA receptor subtypes and benzodiazepine use, misuse, and abuse

[[La...]]

The full title of this American review is "GABA_A receptor subtypes and benzodiazepine use, misuse, and abuse".

https://pubmed.ncbi.nlm.nih.gov/36713896/ 

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 GABA_A receptor subtypes. While there is ample evidence that subtype-selective GABA_A 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 GABA_A receptor subtypes in each of these areas. The reviewed studies suggest that α1-containing GABA_A 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 GABA_A 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 GABA_A 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 GABA_A receptor subtypes in these processes, to establish an informed foundation for preclinical and clinical efforts.

Full Paper:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9879605/

[[Na...]]

Interesting paper. More evidence that the α1 subunit might be the culprit for the development of tolerance and withdrawal effects.

There's been a couple of papers that have implicated α1 now.

[[La...]]

Were they pointing to something else before? Or are they just getting deeper into the nitty-gritty of this particular issue?