Jack Davis

Background: Adolescence is a crucial developmental phase between ages 10 and 19, characterized by significant brain development and maturation.¹ According to the 2022 National Survey on Drug Use and Health, 6.8% of adolescents aged 12-17 reported alcohol use in the past month, with 3.2% engaging in binge drinking. Binge drinking is a pattern of alcohol consumption that raises an individual’s Blood Alcohol Concentration to 0.08%, 0.08 g/dL, in under two hours and is linked to profound changes in the brain, particularly in the hippocampus, a region critically involved in memory and learning.^2-5 Ethanol affects this area by altering the activity of glutamatergic N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which are essential for the regulation of synaptic mechanisms like long-term potentiation (LTP) and depression (LTD), fundamental to learning and memory consolidation.^3-5

Objective: This narrative literature review investigates how AMPA and NMDA receptors in the hippocampus adapt to binge ethanol exposure during adolescence and how these adaptations affect synaptic plasticity.

Search Methods: An online search was performed in the PubMed database for articles published from 2018 to 2024, focusing on keywords such as “adolescent binge drinking,” “ethanol,” “NMDA receptors,” “AMPA receptors,” “hippocampus,” and “synaptic plasticity.”

Results: In experiments with adolescent male Sprague Dawley rats, two intraperitoneal injections of EtOH (3g/kg; 15% v/v), administered 9 hours apart to simulate binge drinking, significantly increased Histone Deacetylase 2 (HDAC2) activity.⁴ This resulted in the overexpression of the GluN2B NMDA receptor subunit, disrupting the typical developmental transition to GluN2A subunits, vital for synaptic maturation and cognitive development.⁴ Electrophysiological studies revealed that this alteration led to compromised synaptic plasticity, evidenced by reduced long-term depression (LTD) and a leftward shift in the Bernstein-Cooper-Munro–like curve.⁴ Pretreatment with Sodium Butyrate (NaB, 600 mg/kg, i.p.), a Histone Deacetylase inhibitor, effectively prevent the EtOH-induced overexpression of GluN2B and the ablation of LTD magnitude.⁴ Similar studies with adolescent male Wistar rats showed that binge ethanol exposure also skewed the balance of AMPA receptor subunits, resulting in a notable increase in GluA2/3 ratio compared to GluA1/2 ratio.⁵ Evidence suggests that this subunit ratio shift, crucial for memory functions, may stem from ethanol-induced inactivation of Glycogen Synthase Kinase 3β (GSK3β), a kinase instrumental in AMPA receptor trafficking during synaptic plasticity.^5,6 Binge ethanol consumption led to significant (P < .01) rises in inactivated GSK3β, AKA pSer9-GSK3β, and One Way ANOVA revealed a significant (P < .001) positive correlation between pSer9-GSK3β levels and working memory errors in the Radial Arm Maze, a test which evaluates hippocampus-dependent spatial learning and memory.⁵

Conclusion: These studies provide evidence that the overexpression of the GluN2B NMDAR subunit after adolescent binge drinking may occur through epigenetic regulation of the K12 site on Histone 4 by EtOH-induced increases in HDAC2 activity.⁴ NaB’s preventive effects further suggest that ethanol’s influence on synaptic and cognitive functions is mediated through HDAC2’s modulation of GluN2B expression, offering a promising avenue for therapeutic interventions against the adverse effects of adolescent binge drinking.⁴ Furthermore, the inactivation of GSK3B likely interferes with synaptic plasticity by promoting the exocytosis (rather than internalization) of AMPA receptors to the neuron surface, thus contributing to the unbalance between the ratios of AMPA receptor subunits and the challenges with LTD following adolescent binge drinking.^5,6

Works Cited:

1. Tetteh-Quarshie S, Risher ML. Adolescent brain maturation and the neuropathological effects of binge drinking: A critical review. Front Neurosci. 2023;16:1040049. Published 2023 Jan 17. doi:10.3389/fnins.2022.1040049
2. SAMSA. Key Substance Use and Mental Health Indicators in the United States: Results from the 2022 National Survey on Drug Use and Health. HHS Publication No. PEP23-07-01-006. Published November 2023. Accessed February 10, 2024.
3. Walker CD, Kuhn CM, Risher ML. The effects of peri-adolescent alcohol use on the developing hippocampus. Int Rev Neurobiol. 2021;160:251-280. doi:10.1016/bs.irn.2021.08.003
4. Drissi I, Deschamps C, Fouquet G, et al. Memory and plasticity impairment after binge drinking in adolescent rat hippocampus: GluN2A/GluN2B NMDA receptor subunits imbalance through HDAC2. Addict Biol. 2020;25(3):e12760. doi:10.1111/adb.12760
5. Contreras A, Polín E, Miguéns M, et al. Intermittent-Excessive and Chronic-Moderate Ethanol Intake during Adolescence Impair Spatial Learning, Memory and Cognitive Flexibility in the Adulthood. Neuroscience. 2019;418:205-217. doi:10.1016/j.neuroscience.2019.08.051
6. Contreras A, Morales L, Del Olmo N. The intermittent administration of ethanol during the juvenile period produces changes in the expression of hippocampal genes and proteins and deterioration of spatial memory. Behav Brain Res. 2019;372:112033. doi:10.1016/j.bbr.2019.112033