Exploring ketamine's reinforcement, cue-induced reinstatement, and nucleus accumbens cFos activation in male and female long evans rats.
Devin P Hagarty, Adam Dawoud, Alfonso Brea Guerrero, Kaynas Phillips, Caroline E. Strong, Sarah Dollie Jennings, Michelle Crawford, Katherine Martinez, Olivia Csernecky, Samantha K Saland, Mohamed Kabbaj
Neuropharmacology September 1, 2024 DOI: 10.1016/j.neuropharm.2024.110008 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Long Evans rats |
| Intervention | Ketamine |
| Dose | 0, 0.125, 0.25, 0.5 mg/kg/infusion |
| Topics | Addiction Esketamine Ketamine |
| Keywords | Dose-response Sex differences Cfos Addiction-risk Sex-differences-behavior Ketamine-dosing Relapse-mechanisms |
| Citations | 6 |
| Key findings | Ketamine has reinforcing effects in both sexes at higher doses, with females showing higher self-administration at the highest dose, and all doses led to cue-induced reinstatement with increased cFos expression in the nucleus accumbens core. |
Abstract
Ketamine (KET), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, has rapid onset of antidepressant effects in Treatment-Resistant Depression patients and repeated infusions are required to sustain its antidepressant properties. However, KET is an addictive drug, and so more preclinical and clinical research is needed to assess the safety of recurring treatments in both sexes. Thus, the aim of this study was to investigate the reinforcing properties of various doses of KET (0-, 0.125-, 0.25-, 0.5 mg/kg/infusion) and assess KET's cue-induced reinstatement and neuronal activation in both sexes of Long Evans rats. Neuronal activation was assessed using the protein expression of the immediate early gene cFos in the nucleus accumbens (Nac), an important brain area implicated in reward, reinforcement and reinstatement to most drug-related cues. Our findings show that KET has reinforcing effects in both male and female rats, albeit exclusively at the highest two doses (0.25 and 0.5 mg/kg/infusion). Furthermore, we noted sex differences, particularly at the highest dose of ketamine, with female rats displaying a higher rate of self-administration. Interestingly, all groups that self-administered KET reinstated to drug-cues. Following drug cue-induced reinstatement test in rats exposed to KET (0.25 mg/kg/infusion) or saline, there was higher cFos protein expression in KET-treated animals compared to saline controls, and higher cFos expression in the core compared to the shell subregions of the Nac. As for reinstatement, there were no notable sex differences reported for cFos expression in the Nac. These findings reveal some sex and dose dependent effects in KET's reinforcing properties and that KET at all doses induced similar reinstatement in both sexes. This study also demonstrated that cues associated with ketamine induce comparable neuronal activation in the Nac of both male and female rats. This work warrants further research into the potential addictive properties of KET, especially when administered at lower doses which are now being used in the clinic for treating various psychopathologies.
Comparable studies
Other preclinical and animal studies on ketamine for addiction, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| R-(-)-ketamine modifies behavioral effects of morphine predicting efficacy as a novel therapy for opioid use disorder. Morphine-dependent rats and mice | 2020 | Preclinical study | |
| The effects of (2R,6R)-hydroxynorketamine on oxycodone withdrawal and reinstatement. Male and female oxycodone-dependent mice | 2023 | Preclinical study | |
| Characterizing the therapeutical use of ketamine for adolescent rats of both sexes: Antidepressant-like efficacy and safety profile. Adolescent rats of both sexes, including naïve and early-life stressed (maternal... | 2025 | Preclinical study | |
| Brain acid sphingomyelinase controls addiction-related behaviours in a sex-specific way. Male and female mice with forebrain ASM overexpression | 2025 | Experimental study | |
| Cannabidiol or ketamine for preventing the impact of adolescent early drug initiation on voluntary ethanol consumption in adulthood. Male and female Sprague-Dawley rats | 2024 | Preclinical study |
Citations in the library
Cited by 4
- Characterizing the therapeutical use of ketamine for adolescent rats of both sexes: Antidepressant-like efficacy and safety profile. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2025
- Effects of Chronic Social Isolation Stress and Alcohol on the Reinforcing Properties of Ketamine in Male and Female Rats. eNeuro March 1, 2025
- Role of accumbens medium spiny neurons subtypes in reinstatement to ketamine cues in male and female Long Evans rats. Neuropharmacology June 6, 2026
- Sex and individual differences in ketamine's effects on alcohol drinking in rats. Alcohol Clin Exp Res March 1, 2026
Cites 14
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- 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
- Ketamine for Bipolar Depression: A Systematic Review The International Journal of Neuropsychopharmacology April 30, 2021
and 9 more in the library