• Changqing Xu, Sijie Tan, Jiaqiang Zhang, Christoph N Seubert, Nikolaus Gravenstein, Colin Sumners, Terrie Vasilopoulos, and Anatoly E Martynyuk.
• Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, USA.
• Psychoneuroendocrinology. 2015 Oct 1; 60: 173-81.

Background1.5 million children under 12 months of age are exposed to general anesthesia annually in the United States alone. Human and especially animal studies provide evidence that exposure to general anesthesia during the early postnatal period may lead to long-term neurocognitive abnormalities via poorly understood mechanisms. We investigated whether an immature stress response system and γ-aminobutyric acid (GABA) type A receptor activities are involved in mediating these abnormalities.MethodsSprague-Dawley rats at postnatal days 4, 5 or 6 were anesthetized with 2.1% sevoflurane for 6h; maternally separated and house reared rats served as controls.ResultsSevoflurane anesthesia markedly increased corticosterone levels in rat pups of both genders. In adulthood, these rats responded to stress with heightened secretion of corticosterone and a greater increase in corticosterone levels in males versus females. Only male rats, previously exposed to neonatal sevoflurane, had a higher frequency of miniature inhibitory postsynaptic currents in CA1 neurons, spent a shorter time in open arms of the elevated plus maze (EPM) and exhibited impaired prepulse inhibition (PPI) of startle. Pretreatment of male rats prior to sevoflurane with the Na(+)-K(+)-2Cl(-) cotransporter inhibitor, bumetanide, or the mineralocorticoid receptor antagonist, RU28318, normalized endocrine responses to stress and the EPM behavior in adulthood, while only those pretreated with bumetanide exhibited normalized PPI of startle responses. Neither bumetanide nor RU28318 altered the effect of sevoflurane on synaptic activity.ConclusionsSevoflurane-enhanced neuronal excitation and elevated corticosteroid levels at the time of anesthesia contribute to the mechanisms initiating neonatal sevoflurane-induced long-term endocrine and neurobehavioral abnormalities.Copyright © 2015 Elsevier Ltd. All rights reserved.

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