Acute administration of the NMDA receptor antagonists ketamine and MK-801 reveals dysregulation of glutamatergic signalling and sensorimotor gating in the Sapap3 knockout mouse model of compulsive-like behaviour.
James J Gattuso, C. Wilson, Anthony J. Hannan, Thibault Renoir
Neuropharmacology August 1, 2023 DOI: 10.1016/j.neuropharm.2023.109689 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | Sapap3 knockout mice, a genetic mouse model of obsessive-compulsive disorder, aged 2-3 months |
| Interventions | Ketamine MK-801 |
| Dose | Ketamine 30 mg/kg; MK-801 0.25 mg/kg |
| Measures | Light-dark box test, grooming scoring, locomotion assay, prepulse inhibition |
| Topics | Esketamine Ketamine |
| Key findings | Sapap3 knockout mice showed anxiety, compulsive grooming, reduced locomotion, and lower body weight at 2-3 months of age. Acute ketamine (30 mg/kg) did not reduce anxiety or grooming. MK-801 (0.25 mg/kg) revealed altered NMDA receptor function and sex-dependent differences in prepulse inhibition, which the authors interpret as evidence of glutamatergic dysfunction relevant to OCD. |
Abstract
Obsessive-compulsive disorder (OCD) is characterised by excessive intrusive thoughts that may cause an individual to engage in compulsive behaviours. Frontline pharmacological treatments (i.e., selective serotonin reuptake inhibitors (SSRIs)) leave approximately 40% of patients refractory to treatment. To investigate the possibility of novel pharmacological therapies for OCD, as well as the potential mechanisms underlying its pathology, we used the Sapap3 knockout (KO) mouse model of OCD, which exhibits increased anxiety and compulsive grooming behaviours. Firstly, we investigated whether administration of the NMDA receptor (NMDAR) antagonist ketamine (30 mg/kg), would reduce anxiety and grooming behaviour in Sapap3 KO mice. Anxiety-like behaviour was measured via time spent in the light component of the light-dark box test. Grooming behaviour was recorded and scored in freely moving mice. In line with previous works conducted in older animals (i.e. typically between 6 and 9 months of age), we confirmed here that Sapap3 KO mice exhibit an anxious, compulsive grooming, hypolocomotive and reduced body weight phenotype even at a younger age (i.e. 2-3 months of age). However, we found that acute administration of ketamine did not cause a reduction in anxiety or grooming behaviour. We then investigated in vivo glutamatergic function via the administration of a different NMDAR antagonist, MK-801 (0.25 mg/kg), prior to locomotion and prepulse inhibition assays. We found evidence of altered functional NMDAR activity, as well as sexually dimorphic prepulse inhibition, a measure of sensorimotor gating. These results are suggestive of in vivo glutamatergic dysfunction and their functional consequences, enabling future research to further investigate novel treatments for OCD.
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
Cited by 8
- Mice lacking the serotonin transporter do not respond to the behavioural effects of psilocybin. European Journal of Pharmacology March 15, 2025
- Shared effects of electroconvulsive shocks and ketamine on neuroplasticity: A systematic review of animal models of depression. Neuroscience & Biobehavioral Reviews September 1, 2024
- Psilocybin reduces grooming in the SAPAP3 knockout mouse model of compulsive behaviour. Neuropharmacology 2025
- Chronic psilocybin administration increases sociability and alters the gut microbiome in male wild-type mice but not in a preclinical model of obsessive-compulsive disorder Neuropharmacology August 21, 2025
- Psilocybin restores social novelty investigation in male SAPAP3 knockout mice and engages prefrontal–hippocampal circuitry Molecular Psychiatry September 17, 2026
and 3 more in the library
Cites 10
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