Long-Term Neurobehavioral Consequences of a Single Ketamine Neonatal Exposure in Rats: Effects on Cellular Viability and Glutamate Transport in Frontal Cortex and Hippocampus

Abstract

The neonatal exposure to general anesthetics has been associated with neuronal apoptosis and dendritic spines morphologic changes in the developing brain. Ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, is widely used in pediatric patients to induce general anesthesia, analgesia, and perioperative sedation. In the present study, we investigated short- and long-term effects of a single ketamine (20 mg/kg, s.c.) neonatal exposure at postnatal day 7 in rats on the hippocampal and frontal cortical cellular viability. Additionally, putative neurochemical alterations and neurobehavioral impairments were evaluated in the adulthood. Ketamine neonatal administration selectively decreased cellular viability in the hippocampus, but not in the frontal cortex, 24 h after the treatment. Interestingly, a single ketamine neonatal exposure prevented the vulnerability to glutamate-induced neurotoxicity in the frontal cortex of adult rats. No short- or long-term damage to cellular membranes, as an indicative of cell death, was observed in hippocampal or cortical slices. However, ketamine induced a long-term increase in hippocampal glutamate uptake. Regarding behavioral analysis, neonatal ketamine exposure did not alter locomotor activity and anxiety-related parameters evaluated in the open-field test. However, ketamine administration disrupted the hippocampal-dependent object recognition ability of adult rats, while improved the motor coordination addressed on the rotarod. These findings indicate that a single neonatal ketamine exposure induces a short-term reduction in the hippocampal, but not in cortical, cellular viability, and long-term alterations in hippocampal glutamate transport, improvement on motor performance, and short-term recognition memory impairment.

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Funding

This research was supported by grants from Brazilian funding agencies Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq #307319/2012-1), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/PVE 052/2012; CAPES-FCT 2014), Programa de Apoio aos Núcleos de Excelência (PRONEX-Project NENASC), Fundação de Apoio à Pesquisa do Estado de Santa Catarina (FAPESC), Instituto Nacional de Ciência e Tecnologia (INCT for Excitotoxicity and Neuroprotection); and by Portuguese funding agencies Fundação para a Ciência e Tecnologia (FCT, Portugal) (Strategic Project 2015-UID/NEU/04539/2013), COMPETE-FEDER (POCI-01-0145-FEDER-007400), Centro 2020 Regional Operational Programmes (CENTRO-01-0145-FEDER-000012: HealthyAging 2020 and CENTRO-01-0145-FEDER-000008: BrainHealth 2020). C.I.T. and R.D.P. are recipient of research fellowship from CNPq.

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Correspondence to Carla Inês Tasca or Frederico C. Pereira.

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Sampaio, T.B., de Oliveira, L.F., Constantino, L.C. et al. Long-Term Neurobehavioral Consequences of a Single Ketamine Neonatal Exposure in Rats: Effects on Cellular Viability and Glutamate Transport in Frontal Cortex and Hippocampus. Neurotox Res 34, 649–659 (2018). https://doi.org/10.1007/s12640-018-9927-x

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Keywords

  • Ketamine
  • Glutamatergic neurotransmission
  • Locomotor activity
  • Memory
  • Neonatal