Cerci Hammons

 Introduction. Alcohol use disorder is one of the most prevalent diseases in the United States, affecting approximately 6.2% of adults, and 2.5% of youth, and comprising 3.8% of global deaths and 4.6% of global disability.¹ The Co-morbidity of alcohol use disorder and psychiatric illness has a staggering 24-37% comorbidity prevalence associated with higher risks of homelessness, suicidality, and more frequent alcohol related hospitalizations.² The co-morbidity development is endorsed by an imbalance of a neurotrophin, known as Brain Derived Neurotrophic Factor (BDNF), which is strongly concentrated in the hypothalamus, amygdala, and neocortex. ³ BDNF is of grave importance as it is needed for development, learning, and regulating the reward pathway through dopamine receptor ratios.¹ Studies show that BDNF levels correlate with the comorbidity between the 2 conditions, and can be altered through single nucleotide polymorphisms (SNPs), and epigenetic mechanisms.^4-6 Methods Two studies, both with comparative control groups referencing mice with differing alcohol ingestion levels.^5,7 Experiment 1: Immunohistochemical assays measuring deacetylation levels secondary to stress exposure over time, with BDNF level affects.⁷ Experiment 2: Immunohistochemical assay. Actin and BDNF directly injected into astrocytes. Normal Valine wildtype and Methionine mutation compared, and alcohol ingestion levels measured.⁵ Results Epigenetic mechanisms include an increase in H3k14a, a histone deacetylase. With any kind of stress exposure histone deacetylase levels showed a 168 +/- 12% increase. ^4,6,8 Deacetylation mechanisms will affect the ARC promoter region in the pro-BDNF gene and is associated with decreased promoter gene expression, secondary to decreased ARC access. ^4,5 This SNP involves a replacement of a Valine to Methionine at position 66 of the BDNF gene altering intracellular trafficking of pro-BDNF on account of the Tropomyosin receptor Kinase B in the Met66 variant. ^5,6,9 This pathway regulates many downstream signaling cascades through microRNAs, altering cAMP and cAMP binding protein which will go on to effect D2/D3 receptor ratios in the reward pathway causing a decreased sensitivity in alcohol withdrawal. ^4,6 This decreased sensitivity results in at least a 4g/kg increase in alcohol consumption by 52+/- 10% of Val66Met variant mice. ^5,6,8 Conclusion Studies show altered BDNF levels can be attributed to the two above mechanisms, further predisposing an individual to a plethora of psychiatric disorders through neuropathic changes. ^4,5 Counteracting methods of the above mechanisms, help normalize BDNF levels, providing hope for new therapeutic strategies to control alcohol abuse, ultimately affecting predisposition to psychiatric disorders. ^6,9

1. Zai, C. C., Manchia, M., Zai, G. C., Woo, J., Tiwari, A. K., Luca, V. D., & Kennedy, J. L. (2018). Association study of BDNF and DRD3 genes with alcohol use disorder in Schizophrenia. Neuroscience Letters, 671, 1–6. doi: 10.1016/j.neulet.2018.01.033
2. Andero, R., Choi, D. C., & Ressler, K. J. (2014). BDNF–TrkB Receptor Regulation of Distributed Adult Neural Plasticity, Memory Formation, and Psychiatric Disorders. Progress in Molecular Biology and Translational Science Molecular Basis of Memory, 169–192. doi: 10.1016/b978-0-12-420170-5.00006-4
3. Han, C., Bae, H., Won, S.-D., Roh, S., & Kim, D.-J. (2015). The relationship between brain-derived neurotrophic factor and cognitive functions in alcohol-dependent patients: a preliminary study. Annals of General Psychiatry, 14(1). doi: 10.1186/s12991-015-0065-z
4. Nubukpo, P., Ramoz, N., Girard, M., Malauzat, D., & Gorwood, P. (2017). Determinants of Blood Brain-Derived Neurotrophic Factor Blood Levels in Patients with Alcohol Use Disorder. Alcoholism: Clinical and Experimental Research, 41(7), 1280–1287. doi: 10.1111/acer.13414
5. Kim, T. Y., Kim, S. J., Chung, H. G., Choi, J. H., Kim, S. H., & Kang, J. I. (2017). Epigenetic alterations of the BDNF gene in combat-related post-traumatic stress disorder. Acta Psychiatrica Scandinavica, 135(2), 170-179. doi: 10.1111/acps.12675
6. Caputi, F., Palmisano, M., D’Addario, C., Candeletti, S., & Romualdi, P. (2015). Effects of acute ethanol exposure on class I HDACs family enzymes in wild-type and BDNF /− mice. Drug and Alcohol Dependence, 155, 68–75. doi: 10.1016/j.drugalcdep.2015.08.015
7. Covington, H., Maze, I., Vialou, V., & Nestler, E. (2015). Antidepressant action of HDAC inhibition in the prefrontal cortex. Neuroscience, 298, 329–335. doi: 10.1016/j.neuroscience.2015.04.030
8. Bohnsack, J. P., Teppen, T., Kyzar, E. J., Dzitoyeva, S., & Pandey, S. C. (2019). The lncRNA BDNF-AS is an epigenetic regulator in the human amygdala in early onset alcohol use disorders. Translational Psychiatry, 9(1). doi: 10.1038/s41398-019-0367-z
9. Warnault, V., Darcq, E., Morisot, N., Phamluong, K., Wilbrecht, L., Massa, S. M., … Ron, D. (2016). The BDNF Valine 68 to Methionine Polymorphism Increases Compulsive Alcohol Drinking in Mice That Is Reversed by Tropomyosin Receptor Kinase B Activation. Biological Psychiatry, 79(6), 463–473. doi: 10.1016/j.biopsych.2015.06.007