Repeated administration of a subanesthetic dose of ketamine results in impaired motor and cognitive behavior and differential expression of hippocampal P2X1 and P2X7 receptors in adult mice.
Teresa Belem Mares-Barbosa, Ares Orlando Cuellar-Santoyo, Victor Manuel Ruiz-Rodríguez, Karen Hernández-Balderas, Osiel González-Hernández, Diana Patricia Portales-Pérez, Ana María Estrada-Sánchez
Behavioural Brain Research March 28, 2025 DOI: 10.1016/j.bbr.2025.115441 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experiment Peer reviewed |
|---|---|
| Population | Young (35 days old) and adult (76 days old) mice |
| Intervention | Ketamine hydrochloride |
| Dose | 30 mg/Kg |
| Duration | 14-day treatment, with behavioral tests 24 hours after last dose |
| Topics | Esketamine Ketamine |
| Keywords | Ca1 Ca3 Dentate gyrus Glua2 Glun1 Nest-building behavior P2x4 Ketamine-effects Age-dependent-response Hippocampal-function Behavioral-neurology |
| Citations | 3 |
| Key findings | Adult mice, but not young mice, showed impaired nest-building and novel object recognition after repeated ketamine, with opposite changes in hippocampal P2X1 and P2X7 protein levels between age groups. |
Abstract
Ketamine hydrochloride serves multiple purposes, including its use as a general anesthetic, treatment for depression, and recreational drug. In studies involving rodents, ketamine is utilized as a model for schizophrenia. However, it is unclear whether age affects the behavioral response induced by repeated ketamine administration and if it modifies the expression levels of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and purinergic receptors (P2X1, P2X4, P2X7). In the present study, we evaluated the effect of intraperitoneal administration of subanesthetic ketamine dose (30 mg/Kg) for fourteen days on young (35 days of age) and adult (76 days of age) mice on different behavioral tests. Nest-building behavior was evaluated during the fourteen-day treatment; short-term memory and social interaction tests were assessed twenty-four hours after the last administration of ketamine. Interestingly, only adult mice treated with ketamine showed impaired nest-building and novel object recognition. In the hippocampus, an area related to memory and cognition, ketamine administration showed no changes in the relative expression of GluN1, P2X4, and P2X7 while increasing GluA2 and P2X1 only in young mice. In contrast, when assessing the protein levels of P2X1 and P2X7 in the hippocampus following ketamine treatment, young mice exhibited a decrease in P2X1 levels while P2X7 levels increased. In contrast, adult mice showed the opposite pattern; P2X1 levels were higher, and P2X7 levels decreased. These results suggest that adult mice are more vulnerable to repeated ketamine administration than young mice and that a differential response of P2X1 and P2X7 might contribute to ketamine-induced behavioral changes.
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 7
- 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
- Reviewing the ketamine model for schizophrenia Journal of Psychopharmacology November 20, 2013
- Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms Neuropsychopharmacology July 24, 2023
- Ketamine Disrupts Frontal and Hippocampal Contribution to Encoding and Retrieval of Episodic Memory: An fMRI Study Cerebral Cortex November 10, 2004
- Ketamine’s rapid antidepressant effects are mediated by Ca2+-permeable AMPA receptors bioRxiv January 16, 2023
and 2 more in the library