Inhibition of GABA Signaling in the Central Amygdala in the Treatment of Alcohol Use Disorder

June 12, 2024 Mohamad Taha

Mohamad Taha

Background: Alcohol use disorder (AUD) is a medical condition that involves the disruption of normal social and occupational life due to excess alcohol consumption.1 11.2% of American adults aged 18 or older, and a further 2.9% of youth aged between 12 and 17 years old, suffer from AUD.2 Globally, AUD contributes to over 3 million deaths annually through several adverse effects such as motor vehicle accidents, cirrhosis, and various cancers including those of the esophagus, oral cavity, and liver.1 Chronic alcohol use is associated with dysfunction of GABA, glutamate, and corticotropin releasing factor transmission in the central amygdala.3 Despite its prevalence, only around 30% of patients with AUD will achieve complete abstinence, and the mechanisms responsible for chronic alcohol induced neuronal changes in GABA signaling in the central amygdala are still not fully understood.1,4 Thus, further research in this area may help with the development of therapies that can reduce subsequent behavioral impacts.

Objective: This study aims to investigate the impact of GABA inhibition within the central amygdala on binge alcohol drinking behavior.

Search Methods: A comprehensive search was conducted on the PubMed database, focusing on articles published between 2018 and 2024, using the keywords “alcohol use disorder,” “GABA signaling,” and “central amygdala.”

Results: Electrophysiology studies on primates revealed that alcohol dependent monkeys exhibited higher baseline presynaptic GABA release compared to the control group.5 Moreover, alcohol consumption was shown to increase inhibitory synaptic currents in non-dependent subjects but did not affect firing levels in the alcohol-dependent group, suggesting tolerance to ethanol enhanced GABA release.5 Another study showed that alcohol-preferring rats exhibited addiction-like behaviors alongside decreased expression of the GABA transporter GAT-3 and downregulation of GABAA receptors in the amygdala, suggesting impaired GABA clearance in alcohol addiction.6 In addition, central administration of oxytocin, via an intracerebroventricular route, in alcohol-dependent rats decreased motivation for alcohol use by inhibiting GABAA receptors in the central amygdala, irrespective of the dose of oxytocin that was used.7 In a study of neuropeptide Y1R+ and GABAergic neurons, silencing of these receptors resulted in reduced binge-like ethanol intake.8 Additionally, chronic alcohol exposure led to an increase of substance P-induced GABA release in the central amygdala of dependent and withdrawn rats, suggesting NK-1R hypersensitivity during withdrawal, which was reversed by NK-1R antagonists.9

Conclusions: Multiple pathways in the central amygdala play an essential role in fine-tuning the levels of GABA.6–9 Dysfunction of these pathways contributes to the development of binge drinking behavior in AUD, and their inhibition results in a drastic decrease in alcohol drinking.6–9 Oxytocin, NK-1R antagonists, and NPY1 pathway inhibition in the central amygdala demonstrated significant GABA inhibition and subsequent reduced binge drinking behavior in animal studies, setting them up as potential targets for the development of new treatments for alcohol dependence.7–9                                        

Works Cited:

  1. Nehring SM, Chen RJ, Freeman AM. Alcohol Use Disorder. Treasure Island (FL): StatPearls Publishing; 2024. https://www.ncbi.nlm.nih.gov/books/NBK436003/
  2. National Institute on Alcohol Abuse and Alcoholism. Understanding Alcohol Use Disorder. Updated January 2024. Accessed March 2 2024. Https://Www.Niaaa.Nih.Gov/Publications/Brochures-and-Fact-Sheets/Understanding-Alcohol-Use-Disorder.
  3. Yang W, Singla R, Maheshwari O, Fontaine CJ, Gil-Mohapel J. Alcohol Use Disorder: Neurobiology and Therapeutics. Biomedicines. 2022;10(5):1192. doi:10.3390/biomedicines10051192
  4. Roberto M, Kirson D, Khom S. The Role of the Central Amygdala in Alcohol Dependence. Cold Spring Harb Perspect Med. 2021;11(2):a039339. doi:10.1101/cshperspect.a039339
  5. Jimenez VA, Herman MA, Cuzon Carlson VC, Walter NA, Grant KA, Roberto M. Synaptic adaptations in the central amygdala and hypothalamic paraventricular nucleus associated with protracted ethanol abstinence in male rhesus monkeys. Neuropsychopharmacology. 2019;44(5):982-993. doi:10.1038/s41386-018-0290-7
  6. Augier E, Barbier E, Dulman RS, et al. A molecular mechanism for choosing alcohol over an alternative reward. Science. 2018;360(6395):1321-1326. doi:10.1126/science.aao1157
  7. Tunstall BJ, Kirson D, Zallar LJ, et al. Oxytocin blocks enhanced motivation for alcohol in alcohol dependence and blocks alcohol effects on GABAergic transmission in the central amygdala. PLoS Biol. 2019;17(4):e2006421. doi:10.1371/journal.pbio.2006421
  8. Companion MA, Gonzalez DA, Robinson SL, Herman MA, Thiele TE. Lateral habenula-projecting central amygdala circuits expressing GABA and NPY Y1 receptor modulate binge-like ethanol intake in mice. Addiction Neuroscience. 2022;3:100019. doi:10.1016/j.addicn.2022.100019
  9. Khom S, Steinkellner T, Hnasko TS, Roberto M. Alcohol dependence potentiates substance P/neurokinin-1 receptor signaling in the rat central nucleus of amygdala. Sci Adv. 2020;6(12). doi:10.1126/sciadv.aaz1050

 

 

 

 

 

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