Nucleus Accumbens (NAc) Dopaminergic D1 Receptor (D1R)-Expressing Medium Spiny Neurons (dMSNs) and their Role in Inducing Reward-Seeking Actions in Opioid Use Disorder
Background: The opioid crisis has been a challenging one to tackle, and deaths from opioid overdose continue to rise.1 Addiction to opioids is centered around firing of dopaminergic (D1/D2) medium spiny neurons (MSNs) in the nucleus accumbens (NAc) after opioid firing of Mu opioid receptors (MORs). 4 Patients recovering from opioid use disorder usually receive a maintenance opioid agonist such as methadone to prevent relapse or abuse of opioids.3 Research shows that there are drug-specific responses of D1-MSNs involved in influencing reward-seeking behavior, suggesting that targeting these MSNs could be an alternative therapeutic route for opioid use disorder.
Objective: In this review, we will discuss the significance of D1-MSNs in triggering reward-seeking behaviors in opioid use disorder, their mechanisms, and subsequent outcomes.
Search Methods: This review was written after an online search for review and primary research articles published between 2017 and 2023 from the PubMed database using the keywords: “opioid use disorder”, “nucleus accumbens”, and “dopaminergic medium spiny neurons”.
Results: While not an opioid, studies indicated that stimulation of the NAc with cocaine increased activity of MSNs with both D1 and D2 receptors, suggesting their involvement in the reward neurocircuitry.6 Furthermore, morphine stimulation of MSNs with dopaminergic receptors triggered reduced expression of D2-MSNs.7 This finding suggests that opioids are cell- and receptor- specific.7 Not only are addictive substances receptor-specific, but the subsequent targets of MSNs are tailored to the subset of dopaminergic receptors targeted. 8 While not an opioid, cocaine stimulus of NAc MSNs showed that D1+MSNs projected to the ventral tegmental area (VTA) and ventral pallidum (VP) of the brain, while D1- (D2) MSNs projected to the VP only.8 Additionally, studies involving mice showed that when drug extinction training was taught to mice conditioned to cocaine, drug-context exposure increased D2-MSN expression while mice who were made to stop cocaine immediately showed an increase in D1-MSN expression following drug-context exposure, suggesting that these neuronal receptor types are responsible for specific outcomes of addiction.9 Finally, a study with fentanyl showed that abstinence from the drug resulted in reduced dendritic complexity on D1-MSNs, and led to negative affective behavior in mice, suggesting that that D1-MSNs induce drug-seeking behavior.10
Conclusion: These studies have shown the significance of DA-MSNs in the reward neurocircuitry of opioid use disorder; specifically, D1-MSN firing is linked to drug-seeking behaviors. By focusing on alleviating the drug-seeking side effects of drug-abstinence using D1-MSNs as a target, new therapies for opioid or fentanyl use disorder could follow.
- Volkow ND, Blanco C. The changing opioid crisis: development, challenges and opportunities. Mol Psychiatry. 2021;26(1):218-233. doi:10.1038/s41380-020-0661-4
- Allichon MC, Ortiz V, Pousinha P, et al. Cell-Type-Specific Adaptions in Striatal Medium-Sized Spiny Neurons and Their Roles in Behavioral Responses to Drugs of Abuse. Front Synaptic Neurosci. 2021;13:799274. Published 2021 Dec 14. doi:10.3389/fnsyn.2021.799274
- Comer SD, Cahill CM. Fentanyl: Receptor pharmacology, abuse potential, and implications for treatment. Neurosci Biobehav Rev. 2019;106:49-57. doi:10.1016/j.neubiorev.2018.12.005
- 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
- Solinas M, Belujon P, Fernagut PO, Jaber M, Thiriet N. Dopamine and addiction: what have we learned from 40 years of research. J Neural Transm (Vienna). 2019;126(4):481-516. doi:10.1007/s00702-018-1957-2
- Soares-Cunha C, de Vasconcelos NAP, Coimbra B, et al. Nucleus accumbens medium spiny neurons subtypes signal both reward and aversion [published correction appears in Mol Psychiatry. 2019 Sep 18;:]. Mol Psychiatry. 2020;25(12):3241-3255. doi:10.1038/s41380-019-0484-3
- McDevitt DS, Jonik B, Graziane NM. Morphine Differentially Alters the Synaptic and Intrinsic Properties of D1R- and D2R-Expressing Medium Spiny Neurons in the Nucleus Accumbens. Front Synaptic Neurosci. 2019;11:35. Published 2019 Dec 20. doi:10.3389/fnsyn.2019.00035
- Baimel C, McGarry LM, Carter AG. The Projection Targets of Medium Spiny Neurons Govern Cocaine-Evoked Synaptic Plasticity in the Nucleus Accumbens. Cell Rep. 2019;28(9):2256-2263.e3. doi:10.1016/j.celrep.2019.07.074
- Roberts-Wolfe D, Bobadilla AC, Heinsbroek JA, Neuhofer D, Kalivas PW. Drug Refraining and Seeking Potentiate Synapses on Distinct Populations of Accumbens Medium Spiny Neurons. J Neurosci. 2018;38(32):7100-7107. doi:10.1523/JNEUROSCI.0791-18.2018
- Fox ME, Wulff AB, Franco D, et al. Adaptations in Nucleus Accumbens Neuron Subtypes Mediate Negative Affective Behaviors in Fentanyl Abstinence. Biol Psychiatry. 2023;93(6):489-501. doi:10.1016/j.biopsych.2022.08.023