Role of accumbens medium spiny neurons subtypes in reinstatement to ketamine cues in male and female Long Evans rats.
Devin P Hagarty, Adam Dawoud, Alfonso Brea Guerrero, Kevin Etienne, Sarah Dollie Jennings, Katherine Martinez, Olivia Csernecky, Kristin J. Schoepfer, Caroline E. Strong, Samantha K Saland, Mohamed Kabbaj
Neuropharmacology June 6, 2026 DOI: 10.1016/j.neuropharm.2026.111067 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Drd1a-iCre and Drd2-iCre transgenic rats |
| Interventions | Designer Receptors Exclusively Activated by Designer Drugs (DREADD hM4Di) |
| Topics | Esketamine Ketamine |
| Key findings | D1R-expressing, but not D2R-expressing, nucleus accumbens medium spiny neurons are important for cue-induced reinstatement of ketamine seeking. |
Abstract
Ketamine, a non-competitive N-Methyl-D-Aspartate receptor antagonist, was approved for use with Treatment-Resistant Depression (TRD) and is currently in clinical trials for treating substance use disorder (SUD), and Post Traumatic Stress Disorder. However, ketamine is an addictive drug, and thus we need to better understand ketamine's mechanism of action in addiction to reliably assess the safety of repeated use as a treatment for several psychopathologies. The nucleus accumbens (NAc), the brain's major reward hub, plays an important role in the salience of drug-related cues. The NAc is comprised of 90-95% GABAergic medium spiny neurons (MSNs) and consists of the Core and Shell. MSNs consist of two distinct subpopulations: Dopamine 1 receptor (D1R) and dopamine 2 receptor (D2R) expressing MSNs that roughly positively and negatively regulate behavior, respectively. However, the cell-type specific role of D1R/D2R-containing MSNs in the NAc and the underlying circuitry mediating ketamine reinstatement remains unknown. To this end, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADD, hM4Di) in Drd1a-iCre and Drd2-iCre transgenic rats to assess the roles of the two distinct NAc MSNs during ketamine cue-induced reinstatement. Our results showed an important role of D1R, but not D2R, NAc MSNs in reinstatement to ketamine cues. Future work will focus on identifying the underlying circuit driving cue-induced reinstatement and roles of the direct and indirect pathways.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 8
- Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial. American Journal of Psychiatry March 29, 2019
- A Single Ketamine Infusion Combined With Motivational Enhancement Therapy for Alcohol Use Disorder: A Randomized Midazolam-Controlled Pilot Trial. American Journal of Psychiatry December 2, 2019
- A Single Ketamine Infusion Combined With Mindfulness-Based Behavioral Modification to Treat Cocaine Dependence: A Randomized Clinical Trial. American Journal of Psychiatry June 24, 2019
- Adjunctive Ketamine With Relapse Prevention–Based Psychological Therapy in the Treatment of Alcohol Use Disorder American Journal of Psychiatry January 11, 2022
- A randomized, double-blind, active placebo-controlled study of efficacy, safety, and durability of repeated vs single subanesthetic ketamine for treatment-resistant depression Translational Psychiatry June 26, 2020
and 3 more in the library