Lindsay Mathys

Background: Alcohol Use Disorder (AUD) is characterized by multiple areas of excessive use of ethanol as outlined in the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5). It is estimated that ~30% of US adults will meet criteria for AUD during their lifetime, with  ~15 million US adults currently meeting this diagnostic.¹ AUD has been linked to genetic factors and is estimated to be 40-70% heritable.^2,3 Research is being conducted into how genetic/epigenetic modifications from ethanol consumption impact susceptibility to AUD by altering dopaminergic receptors thereby exacerbating the positive reinforcement cycle underlying the transition from alcohol use to AUD.^2,3,4 The dopamine deficiency hypothesis, supported by numerous clinical and pre-clinical studies, suggests that the dopaminergic reward system compounds an individual’s craving for and compulsion to consume alcohol which contributes to AUD susceptibility and relapse during periods of sobriety.⁴ Dopamine 2 receptors (D2R) and their corresponding gene, Drd2, have been a focus of recent research based due to their focal position in the brain’s striatum combined with their potential to impact addictive behaviors.^4,5

Objective: In this narrative review, we explored the reinforcement of the dopamine deficiency hypothesis by observing chronic ethanol consumption changes in D2R and Drd2 in rats, monkeys, and humans.

Search Methods: An online search was conducted using the PubMed database from 2018-2023 using the following keywords: “alcohol use disorder”, “dopamine”, “D2R”, “Drd2”.

Results: Studies indicate that long-term ethanol consumption diminishes dopaminergic transmission by altering expression of D2R within the brain’s mesolimbic pathway. Significant decreases were noted in overall D2R expression of rats following a 12-week IAE20 model and in longer-lived non-human primate models upon 12-14 months of chronic ethanol consumption.^4,6 Alcohol consumption also had a significant stimulatory effect on Drd2 knockout (KO) mice tested for Loss of Righting Reflex (LORR) and KO mice’s increase in ethanol preference despite negative reinforcement.⁵ A human study found significant increases in Drd2 gene expression within the bloodstream of AUD patients undergoing withdrawal, as well as, increased alcohol craving compared with non-abstinent controls.⁷ Dose-dependent self-administration of D2 antagonist, sulpiride, to rats showed a significant decrease in lever-demand responses compared to sessions of alcohol administering sessions, demonstrating how D2R specific therapy can be used to minimize consumption and inhibit the positive feedback loop of dopaminergic deficiency.⁸ Due to compensatory upregulation of dopaminergic receptors, broad-spectrum therapy, using dopaminergic partial agonist aripiprazole, was also examined and was found to be effective in highly susceptible humans with AUD .^4,5,9

Conclusions: These studies demonstrated that ethanol consumption leads to downregulation in D2R, and that diminished D2R and Drd2 can be linked to increased stimulation and alcohol craving, reinforcing the dopamine deficiency hypothesis. Due to compensatory dopaminergic upregulations, both D2R specific and broad-spectrum therapies should be considered. Further research is needed regarding sex differences in dopaminergic response to chronic alcohol consumption and pharmacological therapies.

Works Cited:

1. Witkiewitz K, Litten RZ, Leggio L. Advances in the science and treatment of alcohol use disorder. Sci Adv. 2019;5(9):eaax4043. Published 2019 Sep 25. doi:10.1126/sciadv.aax4043
2. Longley MJ, Lee J, Jung J, Lohoff FW. Epigenetics of alcohol use disorder-A review of recent advances in DNA methylation profiling. Addict Biol. 2021;26(6):e13006. doi:10.1111/adb.13006
3. Bohnsack JP, Pandey SC. Histone modifications, DNA methylation, and the epigenetic code of alcohol use disorder. Int Rev Neurobiol. 2021;156:1-62. doi:10.1016/bs.irn.2020.08.005
4. Feltmann K, Borroto-Escuela DO, Rüegg J, et al. Effects of Long-Term Alcohol Drinking on the Dopamine D2 Receptor: Gene Expression and Heteroreceptor Complexes in the Striatum in Rats. Alcohol Clin Exp Res. 2018;42(2):338-351. doi:10.1111/acer.13568
5. Bocarsly M.E., da Silva e Silva D., Kolb V., et al. A Mechanism Linking Two Known Vulnerability Factors for Alcohol Abuse: Heightened Alcohol Stimulation and Low Striatal Dopamine D2 Receptors. Cell Reports. 2019;29(5). doi:10.1016/j.celrep.2019.09.059
6. Salinas, A.G., Mateo, Y., Carlson, V.C.C. et al. Long-term alcohol consumption alters dorsal striatal dopamine release and regulation by D2 dopamine receptors in rhesus macaques. Neuropsychopharmacology. 46, 1432–1441 (2021). https://doi.org/10.1038/s41386-020-00938-8
7. Hillemacher T, Rhein M, Burkert A, et al. DNA-methylation of the Dopamin Receptor 2 Gene is Altered during Alcohol Withdrawal. Eur Neuropsychopharmacology. 2019;29(11):1250-1257. doi:10.1016/j.euroneuro.2019.09.002
8. Engleman EA, Ingraham CM, Rodd ZA, Murphy JM, McBride WJ, Ding ZM. The reinforcing effects of ethanol within the prelimbic cortex and ethanol drinking: Involvement of local dopamine D2 receptor-mediated neurotransmission. Drug Alcohol Depend. 2020;214:108165. doi:10.1016/j.drugalcdep.2020.108165
9. Schacht JP, Voronin KE, Randall PK, Anton RF. Dopaminergic Genetic Variation Influences Aripiprazole Effects on Alcohol Self-Administration and the Neural Response to Alcohol Cues in a Randomized Trial. Neuropsychopharmacology. 2018;43(6):1247-1256. doi:10.1038/npp.2017.298