Macy Meyer

Background: The central nucleus of the amygdala integrates information about one’s state and is positioned appropriately to take part in regulating both anxiety and alcohol interactions.¹ Those with anxiety or stress disorders have a more hyperactive amygdala under regular conditions, and this type of hyperactive response is exaggerated and expressed even more in response to negative stimuli.²  Alcohol effects adolescents differently than adults due to the plasticity and continuing development of the adolescent’s brain. Research is being done to see what parts of the brain, specifically the amygdala, was damaged and how it contributes to future Alcohol Use Disorder and Anxiety Disorder. Alcohol Use Sisorder is 50% heritable and 50% attributed to environmental factors.³ Anxiety disorders are approximately 30% heritable as seen in twin studies, but genome-wide association studies have yet to find any specific gene that is significantly associated with anxiety, which implicates environmental and epigenetic factors for playing a strong role in incidence.²

Objective: In this narrative review, we examined the different mechanisms by which adolescent intermittent alcohol abuse epigenetically changed the amygdala and how this contributed to future alcohol use and anxiety behaviors.

Search Methods: On the PubMed database, a search was conducted from 2017-2023 using keywords “adolescent alcohol”, “anxiety”, “amygdala”, “alcohol use disorder”, and “epigenetics”.

Results: Epigenetic modifications are found on the promotor regions of the synaptic plasticity-associated genes of the Arc protein in the central amygdala.⁴ Arc eRNA expression in the central amygdala directly regulates anxiety-like behaviors. Decreased expression led to a long-lasting decrease in synapses in the central and medial nuclei in the amygdala causing a decrease in the expression of Arc eRNA and mRNA.⁴ In a different experiment, the amount of methylation and protein expression were measured in the amygdala with a reference to anxiety behavior measurements.⁴ Epigenetic modifications post AIE were seen in protein 45 Gadd45g mRNA, Dnmt3b mRNA, and DNA methyl transferase.⁵ As adults the experimental group showed increase Dnmt3b mRNA expression and DNA methyltransferase activity and decreased protein 45 Gadd45g mRNA expression was decreased.⁵ Trying to correct epigenetic modification at the Arc SARE site using dCas-9P-300 histone acetylation did not see a significant decrease in anxiolysis, but experimenters say not enough was edited.⁶ Changes in the CRF1 system in the medial central amygdala were seen with pre-natal alcohol abuse.⁷

Conclusions: The decrease in expression of Arc eRNA and mRNA showed an increase in anxiety behaviors.⁴ The changes in the DNA methylation help to explain the change in phenotype and behavior of adults who experienced binge like alcohol exposure as children and currently are suffering from alcohol-use and anxiety problems.⁵ The medication, Rolapitant, antagonizes NFK-1 which targets CRF in the medial nucleus of the amygdala has been shown to decrease anxiety behavior and help with withdrawal symptoms.⁸

Works Cited:

1. Walker LC. A balancing act: the role of pro- and anti-stress peptides within the central amygdala in anxiety and alcohol use disorders. J Neurochem. 2021;157(5):1615-1643. doi:10.1111/jnc.15301
2. Bartlett AA, Singh R, Hunter RG. Anxiety and Epigenetics. Adv Exp Med Biol. 2017;978:145-166. doi:10.1007/978-3-319-53889-1_8
3. Kranzler HR, Soyka M. Diagnosis and Pharmacotherapy of Alcohol Use Disorder: A Review. JAMA. 2018;320(8):815-824. doi:10.1001/jama.2018.11406
4. Kyzar EJ, Zhang H, Pandey SC. Adolescent Alcohol Exposure Epigenetically Suppresses Amygdala Arc Enhancer RNA Expression to Confer Adult Anxiety Susceptibility. Biol Psychiatry. 2019;85(11):904-914. doi:10.1016/j.biopsych.2018.12.021
5. Sakharkar AJ, Kyzar EJ, Gavin DP, et al. Altered amygdala DNA methylation mechanisms after adolescent alcohol exposure contribute to adult anxiety and alcohol drinking. Neuropharmacology. 2019;157:107679. doi:10.1016/j.neuropharm.2019.107679
6. Bohnsack JP, Zhang H, Wandling GM, et al. Targeted epigenomic editing ameliorates adult anxiety and excessive drinking after adolescent alcohol exposure. Sci Adv. 2022;8(18):eabn2748. doi:10.1126/sciadv.abn2748
7. Rouzer SK, Diaz MR. Moderate prenatal alcohol exposure modifies sex-specific CRFR1 activity in the central amygdala and anxiety-like behavior in adolescent offspring. Neuropsychopharmacology. 2022;47(12):2140-2149. doi:10.1038/s41386-022-01327-z
8. Kokhan VS, Anokhin PK, Abaimov DA, Shamakina IY, Soldatov VO, Deykin AV. Neurokinin-1 receptor antagonist rolapitant suppresses anxiety and alcohol intake produced by repeated withdrawal episodes. FEBS J. 2022;289(16):5021-5029. doi:10.1111/febs.16400