Alwin Alias

 Introduction. Alcohol Use Disorder (AUD) is a psychiatric diagnosis that encompasses countless different manifestations of alcohol abuse². Wernicke-Korsakoff syndrome (WKS) is a clinically observable manifestation of AUD that initially presents with physical symptoms and chronically progresses to display severe cognitive deficits⁵. The hallmark sign used to diagnose this condition is a thiamine (vitamin B₁) deficiency^5,6. Recent studies have found that chronic alcohol abuse causes damage to NMDA receptors located in the hippocampus, specifically by causing excitotoxicity of the GluN2B subunit of the NMDA receptor^1,4. It was also found that combining chronic alcohol abuse with a physiological deficiency of thiamine results in additive effects that contribute to detriment in the hippocampus that manifests as reductions in spatial processing and general cognitive ability⁶. NMDA receptor antagonists like Memantine were found to have effects that counteract this synergistic detriment caused by chronic alcohol abuse and thiamine deficiency³. Methods. Rat models were used to demonstrate the detrimental effects of GluN2B excitotoxicity, alcohol abuse and thiamine deficiency on the hippocampus^1,4,5,6. Hippocampal samples were obtained at various intervals with varied combinations of the treatments which included EtOH to simulate chronic alcohol abuse and standardized diets with an added variable of thiamine deficiency^1,4,5,6. Hippocampal samples obtained from the rats were used to study long-term depression, GluN2B sensitivity  and brain-derived neurotrophic factor (BDNF) levels^1,4,5,6. Memantine’s effects were studied by administration of the forced swimming test, elevated-plus maze test, passive-avoidance test and open field test before and after treatment³. Results. Studies of GluN2B subunit post-EtOH treatment found that there was significantly increased firing of excitatory potentials from this subunit (−18.1 ± 3.6%)*, supporting the hypothesis that the GluN2B subunit becomes increasingly sensitive with chronic alcohol abuse^1,4. Rats that were administered both EtOH treatments and thiamine-deficient diets had more pronounced decreases in hippocampal BDNF levels as compared to other treatment groups⁶. EtOH-treated, thiamine-deficient rats had increased levels of anxiety and incidences of depression-like states with the four cognitive tests mentioned above, but Memantine administration was seen to ameliorate these effects to a large extent (1141.39 ± 25.06)³. Conclusions. It is best to think of these mechanisms as a “domino effect.” AUD is a psychiatric diagnosis that often manifests physiologically as conditions like WKS. These physiological manifestations include quantifiable deficits such as thiamine deficiency and GluN2B excitotoxicity. These deficits synergistically cause deterioration of hippocampus-related learning and memory. NMDA receptor antagonists like Memantine have the underappreciated potential to counteract this learning and memory deterioration to a large extent.

1. 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. 2019:e12760.
2. Kranzler HR, Soyka M. Diagnosis and Pharmacotherapy of Alcohol Use Disorder: A Review. Jama. 2018;320(8):815-824.
3. Makino M, Takahashi-Ito K, Murasawa H, Pawlak A, Kashimoto Y, Kitano Y. Memantine ameliorates learning and memory disturbance and the behavioral and psychological symptoms of dementia in thiamine-deficient mice. Pharmacol Biochem Behav. 2019;183:6-13.
4. Mira RG, Tapia-Rojas C, Perez MJ, et al. Alcohol impairs hippocampal function: From NMDA receptor synaptic transmission to mitochondrial function. Drug Alcohol Depend. 2019;205:107628.
5. Sanvisens A, Zuluaga P, Fuster D, et al. Long-Term Mortality of Patients with an Alcohol-Related Wernicke-Korsakoff Syndrome. Alcohol Alcohol. 2017;52(4):466-471.
6. Vedder LC, Hall JM, Jabrouin KR, Savage LM. Interactions between chronic ethanol consumption and thiamine deficiency on neural plasticity, spatial memory, and cognitive flexibility. Alcohol Clin Exp Res. 2015;39(11):2143-2153.