Ketamine administration induces early and persistent neurochemical imbalance and altered NADPH oxidase in mice

Abstract

Administration in adulthood of subanaesthetic doses of ketamine, an NMDA receptor (NMDA-R) antagonist, is commonly used to induce psychotic-like alterations in rodents. The NADPH oxidase (NOX) derived-oxidative stress has been shown to be implicated in ketamine-induced neurochemical dysfunctions and in the loss of parvalbumin (PV)-positive interneurons associated to the administration of this NMDA receptor antagonist in adult mice. However, very few data are available on the effects of early ketamine administration and its contribution to the development of long-term dysfunctions leading to psychosis.Here, by administering a subanaesthetic dose of ketamine (30 mg/kg i.p.) to mice at postnatal days (PNDs) 7, 9 and 11, we aimed at investigating early neurochemical and oxidative stress-related alterations induced by this NMDA-R antagonist in specific brain regions of mice pups, i.e. prefrontal cortex (PFC) and nucleus accumbens (NAcc) and to assess whether these alterations lasted until the adult period. To this purpose, we evaluated glutamatergic, glutamine and GABAergic tissue levels, as well as PV amount in the PFC, both two hours after the last ketamine injection (PND 11) and at 10 weeks of age. Dopamine (DA) tissue levels and DA turnover were also evaluated in the NAcc at the same time points. Levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), a reliable biomarker of oxidative stress, as well as of the free radical producers NOX1 and NOX2 enzymes, were also assessed in both PFC and NAcc of ketamine-treated pups and adult mice.Ketamine-treated pups showed increased cortical levels of glutamate (GLU) and glutamine, as well as similar GABA amount compared to controls, together with an early reduction of cortical PV levels. In the adult period, the same was observed for GLU and PV, whereas GABA levels were increased and no changes in glutamine amount were detected. Ketamine administration in early life induced a decrease in DA tissue levels and an increase of DA turnover which were also detectable at 10 weeks of age. These alterations were accompanied by 8-OHdG elevations in both PFC and NAcc at the two considered life stages. The expression of NOX1 was significantly reduced in these brain regions following ketamine administration at early life stages, while, in the adult period, significant elevation of this enzyme was observed. Levels of NOX2 were found increased at both time points.Our results suggest that an early increase of NOX2-derived oxidative stress may contribute to the development of neurochemical imbalance in PFC and NAcc, induced by ketamine administration. Modifications of NOX1 expression might represent, instead, an early response of the developing brain to a neurotoxic insult, followed by a later attempt to counterbalance ketamine-related detrimental effects.