Balance of Activity of D1Rs and D2Rs on Medium Spiny Neurons in the Striatum Can Explain Persistence of Alcohol Seeking Behavior in Alcohol Use Disorder
Background: Alcohol use disorder is a significant contributor to preventable death and economic burden both in the United States and globally.1 There is a large treatment gap due to the stigma surrounding mental health disorders and even individuals that receive treatment continue to have high relapse rates.2 Understanding the plasticity of neuronal circuitry of medium spiny neurons in the striatum and manipulation of dopamine receptors can provide potential therapeutic options for alcohol use disorder.3-5
Objectives: In this review, the plasticity of medium spiny neurons was examined in response to long term alcohol consumption. The effects of dopamine receptor modulation were also explored to determine the impact on alcohol consumption and behavioral patterns.
Search Methods: The online database, Pubmed, was searched using the keywords, “D1 receptors,” “D2 receptors,” “medium spiny neurons,” and “alcohol use disorder,” between the years 2017-2023.
Results: Studies that examined the density of D2 receptor complexes in the striatum indicated that long-term alcohol use in mice decreased the amount of D2 receptor complexes found in the dorsal striatum.3 Evaluating levels of mRNA showed decreased levels of the long isoform of D2 receptor in the alcohol drinking group of mice.3 Alcohol was also shown to increase glutamatergic transmission in D1-MSNs while increasing GABAergic transmission in D2-MSNs.4 Given that D1-MSNs are considered to be the “go” mediators while D2-MSNs are the “no-go” mediators, this study showed alcohol increased excitatory currents in the “go” mediators and increased inhibitory currents in the “no-go” mediators.4 Using DREADDs, D1-MSNs were able to be selectively excited which showed a increase in alcohol consumption and alcohol preference while selective excitation of D2-MSNs showed a decrease in alcohol consumption and preference in mice.4 A study that explored behavioral patterns in mice, used compound 21 to activate astrocytes to selectively inhibit D1-MSNs and excite D2-MSNs.6 This resulted in a decrease in habitual behavior, defined by continued nose-poking in a devalued condition, and a shift towards goal directed behavior, which was defined by continued nose-poking in a valued condition.6 This demonstrated potential therapeutic research avenues by manipulating D1-MSN and D2-MSN in the striatum to change behavioral patterns.6
Conclusion: Studies showed that alcohol consumption impacted dopamine receptor levels on medium spiny neurons by decreasing D2 receptor complex levels in the striatum. This resulted in a decrease in the “no-go” transmission that is provided by D2-MSNs. Additionally, studies showed D1-MSNs and D2-MSNs can be manipulated to change alcohol consumption behaviors. The balance of activity of D1-MSNs and D2-MSNs can be modulated to potentially abolish habitual behavior and promote goal-directed behavior. While the murine model shows potential in future treatment options for alcohol use disorder, further research needs to be conducted to determine how this research translates to human clinical medicine.
- Salib AN, Ho AL, Sussman ES, Pendharkar AV, Halpern CH. Neuromodulatory Treatments for Alcohol Use Disorder: A Review. Brain Sci. 2018;8(6):95. Published 2018 May 28. doi:10.3390/brainsci8060095
- Carvalho AF, Heilig M, Perez A, Probst C, Rehm J. Alcohol use disorders. Lancet. 2019;394(10200):781-792. doi:10.1016/S0140-6736(19)31775-1
- 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
- Cheng Y, Huang CCY, Ma T, et al. Distinct Synaptic Strengthening of the Striatal Direct and Indirect Pathways Drives Alcohol Consumption. Biol Psychiatry. 2017;81(11):918-929. doi:10.1016/j.biopsych.2016.05.016
- Wise RA, Jordan CJ. Dopamine, behavior, and addiction.J Biomed Sci. 2021;28(1):83. Published 2021 Dec 2. doi:10.1186/s12929-021-00779-7
- Kang S, Hong SI, Lee J, et al. Activation of Astrocytes in the Dorsomedial Striatum Facilitates Transition From Habitual to Goal-Directed Reward-Seeking Behavior. Biol Psychiatry. 2020;88(10):797-808. doi:10.1016/j.biopsych.2020.04.023