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

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 alpha-amino-3-hydroxy-5-methyl-4isoxazolepropionic 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.