Effects of Chronic Social Isolation Stress and Alcohol on the Reinforcing Properties of Ketamine in Male and Female Rats.
Sarah D Jennings, Devin P Hagarty, Jordan Logue, Michelle Crawford, Samantha K Saland, Mohamed Kabbaj
eNeuro March 1, 2025 DOI: 10.1523/ENEURO.0452-24.2025 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Male and female rats |
| Interventions | social isolation intermittent access to 20% alcohol intravenous ketamine self-administration |
| Duration | 12 weeks of social isolation and alcohol access, then ketamine self-administration sessions |
| Topics | Ketamine Esketamine |
| Keywords | Alcohol Isolation Nucleus accumbens Spines Stress Addiction research Sex differences Substance interactions Behavioral science |
| Citations | 1 |
| Key findings | A history of social isolation and alcohol exposure modulates the reinforcing properties of ketamine in a sex-dependent manner, with females self-administering more ketamine than males and alcohol increasing intake in females, while isolation or alcohol independently increased intake in males. |
Abstract
While ketamine, an NMDA receptor antagonist, is effective in treating major depression, studies have not addressed the safety of repeated ketamine infusions in depressed patients with comorbid alcohol use disorder (AUD). In this study, we aimed to determine whether a history of chronic social isolation and alcohol exposure alter the reinforcing properties of ketamine in male and female rats. Rats were pair-housed or socially isolated for 12 weeks and underwent intermittent access to 20% alcohol. Subsequently, rats underwent intravenous ketamine self-administration under a fixed ratio 1 schedule, followed by extinction training and one session of cue-induced reinstatement. Dendritic spine morphology was examined in the nucleus accumbens, an important area implicated in reward and motivation. Our results show that females self-administered more ketamine than males, a history of alcohol increased ketamine intake in females, and a history of isolation or alcohol independently increased ketamine intake in males. All experimental groups showed similar extinction patterns and reinstatement to ketamine cues. A pattern emerged similar to ketamine self-administration behaviors, where isolation increased the number of immature spines in males, a change that was attenuated in isolated alcohol drinkers, and a history of alcohol increased the number of immature spines in females. Our results suggest that a history of isolation and alcohol modulate the reinforcing properties of ketamine in a sex-dependent manner. This underscores the importance of considering sex differences and a history of alcohol use when employing ketamine to treat various psychopathologies, including major depression.
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 13
- 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
- Adjunctive Ketamine With Relapse Prevention–Based Psychological Therapy in the Treatment of Alcohol Use Disorder American Journal of Psychiatry January 11, 2022
- Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit Molecular Psychiatry November 21, 2017
- Changes in synaptic markers after administration of ketamine or psychedelics: a systematic scoping review Frontiers in Psychiatry June 26, 2023
- Exploring ketamine's reinforcement, cue-induced reinstatement, and nucleus accumbens cFos activation in male and female long evans rats. Neuropharmacology September 1, 2024
and 8 more in the library