Biology:GABA receptor antagonist

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GABA[1] gamma-aminobutyric acid (GABA) is a key chemical messenger or a neurotransmitter in the central nervous system, that significantly inhibits neuronal transmission. GABA calms the brain and controls several physiological processes, such as stress, anxiety, and sleep. GABAA receptors are a class of ionotropic receptors[2] that are triggered by GABA. They are made up of five subunits that are assembled in various configurations to create distinct receptor subtypes. The direct influx of chloride ions[3] causes rapid inhibitory responses. GABAB receptors are another type of metabotropic receptor[4] that modifies intracellular signaling pathways to provide slower, sustained inhibitory responses. At synapses, GABAA receptors facilitate rapid inhibitory neurotransmission, whereas GABAB receptor which comprise GABA B1 and GABA B2 subunits—control neurotransmitter release and cellular excitability over a longer period of time. As these. These unique qualities help explain the various ways that GABAergic neurotransmission controls brain communication and neuronal function.

GABAA receptors[5] are categorized into many subtypes according to the individual subunits that comprise the receptor. The most prevalent subtypes are those that have either the β2 or β3 subunits, or the α1, α2, α3, or α5 subunits.

GABA receptor antagonists are drugs that inhibit the action of GABA. In general these drugs produce stimulant and convulsant effects, and are mainly used for counteracting overdoses of sedative drugs. Examples include bicuculline, securinine and metrazol, and the benzodiazepine GABAA receptor antagonist flumazenil. Other agents which may have GABAA receptor antagonism include the antibiotic ciprofloxacin, tranexamic acid,[6] thujone,[7] ginkgo biloba,[8] and kudzu.[9]

Benzodiazepine GABAA receptor[5] Every GABA subtype one of a receptor's distinctive characteristics is its distribution across the brain, which varies, as does its sensitivity to GABA and other modulators. The actions of medications that target GABAA receptors, such as benzodiazepines, may be significantly impacted by these variations in receptor subtype characteristics. Benzodiazepines, for instance, have the ability to bind to GABAA receptors with the α1 subunit preferentially, which is assumed to be the cause of these medications' sedative and anxiolytic effects. Nevertheless, other effects of benzodiazepines, such their propensity for misuse and the emergence of tolerance and dependence, can be related to different subtypes of GABAA receptors. Because benzodiazepines may be addictive and because their non-medical use can have detrimental consequences and results, abuse and misuse of these drugs have become important public health problems. Here are some important things to think about: 1. Abuse vs. Misuse: The deliberate, non-medical use of benzodiazepines to produce a euphoric or intoxicated effect is commonly referred to as abuse. Contrarily, misuse refers to a wider variety of actions, such as utilizing benzodiazepines for reasons other than its intended medical use, taking larger dosages than recommended, or using them without a prescription. 2. Risk variables: A number of variables, such as a history of substance addiction, co-occurring mental health conditions, easy availability to the medications, and a lack of knowledge about their addictive potential, contribute to the abuse and misuse of benzodiazepines. 3. Consequences: Abuse and misuse of benzodiazepines can result in a number of unfavorable outcomes, such as overdose, accidents, poor cognitive function, physical and psychological dependency, and legal problems. 4. Co-occurring Substance Use: Opioids and alcohol are the two drugs that are most frequently used with benzodiazepines to cause abuse. This polydrug usage raises the possibility of negative results and increases the hazards connected with benzodiazepine misuse. 5. Impact on Public Health: Abuse and misuse of benzodiazepines create problems for social services, law enforcement, and healthcare systems as well as add to the overall burden of drug use disorders. 6. Prevention and Intervention: Methods to combat the abuse and misuse of benzodiazepines include educating the public about the dangers of using them for purposes other than medicine, enhancing prescription practices, implementing prescription monitoring programs, and providing evidence-based treatment to those who are afflicted with benzodiazepine use disorders.

Recent Investigated study on GABAA Receptor α1 subunit[1] A study that used mice under forced swimming stress (FSS)[10] examined the molecular processes behind ketamine's quick antidepressant effects. Pre-swimming stress is shown to cause depression-like behavior and lower hippocampal GABA levels; however, ketamine injections alone can counteract these effects and link hippocampal GABA levels to antidepressant-like effects. Ketamine causes alterations in astrocyte plasticity, increases GABA production and metabolism, and downregulates the GABA receptor α1 subunit. The production, metabolism, and plasticity of astrocytes are all impacted by the pharmacological manipulation of GABAA receptors. According to the study, ketamine's quick antidepressant activity is caused by altered GABA transporters and enzymes, downregulation of the GABAA receptor α1 subunit, enhanced GABA synthesis, and finally increased GABA and ATP levels in the hippocampus .GABA, ATP, and astrocytes are related, highlighting the function of astrocytic plasticity in depression and ketamine's antidepressant properties. According to the study, GABAergic transmission via GABA The hippocampus's receptor α1 subunit plays a crucial role in the fast-acting antidepressant-like effects of ketamine in mice. The necessity for more research into the molecular pathways and the possible role of ketamine enantiomers are among the limitations.

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References

  1. ↑ 1.0 1.1 Tang, Xiao-Hui; Diao, Yu-Gang; Ren, Zhuo-Yu; Zang, Yan-Yu; Zhang, Guang-Fen; Wang, Xing-Ming; Duan, Gui-Fang; Shen, Jin-Chun et al. (2023). "A role of GABAA receptor α1 subunit in the hippocampus for rapid-acting antidepressant-like effects of ketamine". Neuropharmacology 225. doi:10.1016/j.neuropharm.2022.109383. PMID 36565851. https://www.sciencedirect.com/science/article/pii/S0028390822004427. 
  2. ↑ Sallard, E.; Letourneur, D.; Legendre, P. (2021). "Electrophysiology of ionotropic GABA receptors". Cellular and Molecular Life Sciences : CMLS 78 (13): 5341–5370. doi:10.1007/s00018-021-03846-2. PMID 34061215. 
  3. ↑ Mihic, S. J.; Harris, R. A. (1997). "GABA and the GABAA Receptor". Alcohol Health and Research World 21 (2): 127–131. PMID 15704348. 
  4. ↑ TERUNUMA M (2018). "Diversity of structure and function of GABAB receptors: A complexity of GABAB-mediated signaling". Proceedings of the Japan Academy. Series B, Physical and Biological Sciences 94 (10): 390–411. doi:10.2183/pjab.94.026. PMID 30541966. 
  5. ↑ 5.0 5.1 Engin, E. (2023). "GABAA receptor subtypes and benzodiazepine use, misuse, and abuse". Frontiers in Psychiatry 13. doi:10.3389/fpsyt.2022.1060949. PMID 36713896. 
  6. ↑ Roman Furtmüller; Michael G Schlag; Michael Berger; Rudolf Hopf; Sigismund Huck; Werner Sieghart; Heinz Redl (April 2002). "Tranexamic Acid, a Widely Used Antifibrinolytic Agent, Causes Convulsions by a γ-Aminobutyric AcidA Receptor Antagonistic Effect". Journal of Pharmacology and Experimental Therapeutics 301 (1): 168–173. doi:10.1124/jpet.301.1.168. PMID 11907171. https://jpet.aspetjournals.org/content/301/1/168.short. Retrieved 1 November 2021. 
  7. ↑ Karin M. Höld; Nilantha S. Sirisoma; Tomoko Ikeda; Toshio Narahashi; John E. Casida (April 2000). "α-Thujone (the active component of absinthe): γ-Aminobutyric acid type A receptor modulation and metabolic detoxification". PNAS 97 (8): 3826–3831. doi:10.1073/pnas.070042397. PMID 10725394. Bibcode: 2000PNAS...97.3826H. 
  8. ↑ Lidija Ivic; Tristan T.J. Sands; Nathan Fishkin; Koji Nakanishi; Arnold R. Kriegstein; Kristian Strømgaard (December 2003). "Terpene Trilactones from Ginkgo biloba Are Antagonists of Cortical Glycine and GABAA Receptors". Journal of Biological Chemistry 278 (49): 49279–49285. doi:10.1074/jbc.M304034200. PMID 14504293. https://www.jbc.org/article/S0021-9258(20)75703-0/fulltext. Retrieved 1 November 2021. 
  9. ↑ Robert M. Swift; Elizabeth R. Aston (March 2015). "Pharmacotherapy for Alcohol Use Disorder: Current and Emerging Therapies". Harvard Review of Psychiatry 23 (2): 122–133. doi:10.1097/HRP.0000000000000079. PMID 25747925. 
  10. ↑ Krishnan, Vaishnav; Nestler, Eric J. (2011). "Animal Models of Depression: Molecular Perspectives". Molecular and Functional Models in Neuropsychiatry. Current Topics in Behavioral Neurosciences. 7. pp. 121–147. doi:10.1007/7854_2010_108. ISBN 978-3-642-19702-4. 

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See also
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