Disruption of psychostimulant-associated memories by single, low dose ketamine in rats.
Neuropharmacology March 11, 2026 DOI: 10.1016/j.neuropharm.2026.110912 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Male Sprague-Dawley rats trained to self-administer cocaine, methamphetamine, fentanyl, or sucrose |
| Intervention | Ketamine |
| Dose | 6 mg/kg |
| Topics | Esketamine Ketamine |
| Key findings | A single 6 mg/kg dose of ketamine given before a novel, but not familiar, memory retrieval session reduced cue-induced reinstatement of cocaine seeking in male rats. The authors suggest this may occur through reduced parvalbumin neuron activation at retrieval, and the effect extended to methamphetamine but not fentanyl or sucrose. |
Abstract
Cocaine and methamphetamine use disorders pose public health concerns due to the high propensity for relapse driven by persistent drug-associated memories. Output from the medial prefrontal cortex (mPFC) regulates relapse and is controlled by parvalbumin (PV) interneurons, which are surrounded by perineuronal nets (PNNs) that support precise PV neuron firing. We previously showed that removal of mPFC PNNs, which reduces PV firing, disrupted reconsolidation of a cocaine self-administration memory when rats were given a novel, but not familiar, memory retrieval session. Ketamine rapidly suppresses PV neuron output, so we tested whether a single low dose (6 mg/kg) administered before or after a familiar or novel memory retrieval session altered cocaine cue reinstatement. Ketamine given prior to the novel, but not familiar, retrieval session reduced cue reinstatement in male Sprague-Dawley rats. In addition, both ketamine treatments combined with a novel retrieval session reduced PNN intensity around PV neurons after cue reinstatement, suggesting that PNN decreases may be unrelated to reinstatement. However, ketamine reduced the number of c-Fos-activated PV neurons immediately after the novel memory retrieval session, indicating that ketamine may reduce reinstatement through reduced PV neuron function at the time of memory retrieval. Ketamine given just prior to a novel memory retrieval session also reduced cue-induced reinstatement in rats trained for methamphetamine, but not fentanyl or sucrose self-administration. Collectively, these studies show that a single, low dose of ketamine combined with a novel memory retrieval reduces psychostimulant-seeking behavior, and may help delineate the mechanisms for ketamine-reduced relapse in psychostimulant use disorders.
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 15
- 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 Journal of Neuroscience April 15, 1997
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
- Psychedelics reopen the social reward learning critical period Nature June 14, 2023
- Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability Molecular Psychiatry April 15, 2021
and 10 more in the library