Subchronic ketamine alters behaviour, metabolic indices and brain morphology in adolescent rats: Involvement of oxidative stress, glutamate toxicity and caspase-3-mediated apoptosis

Abstract

Ketamine is a dissociative anaesthetic agent whose recreational use amongst adolescents and young adults is reaching epidemic proportions in a number of countries. While animal studies have examined the long-term detrimental effects of early-life ketamine exposure, there is a paucity of information on the immediate effects of ketamine following subchronic administration in the adolescence period.Adolescent rats were assigned into four groups of 10 animals each, administered intraperitoneal (i.p) injections of vehicle or one of three doses of ketamine (7.5, 15 or 30 mg/kg daily) for 8 weeks, and then exposed to behavioural paradigms. Rats were then euthanised after an overnight fast, and blood taken was used for measurement of metabolic indices. The brains were dissected out and either homogenised for estimation of neurochemical parameters, or processed for histological and immunohistochemical studies.Results showed that subchronic administration of ketamine was associated with a lesser weight gain inspite of an increase in food intake across the treatment groups. There was a dose-dependent increase in open-field novelty-induced behaviours, a decline in spatial working-memory, and an anxiolytic effect in the elevated-plus maze. There was associated derangement of serum triglyceride, and increase in brain glutamate levels, acetylcholinesterase activity, plasma/brain oxidative stress parameters, caspase-3 activity and biochemical indices of hepatic and renal function. Ketamine administration was also associated with neurodegenerative changes in the cerebral cortex, hippocampus, cerebellum and the pons. In conclusion, subchronic administration of ketamine to adolescent rats was associated with dose-related memory loss, oxidative stress and possibly caspase-3 mediated neurodegenerative changes.