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BackgroundIn rodents, the period of increased vulnerability to the developmental effects of general anesthetics coincides with the period of age-specific organizing (masculinizing) effects of the major female sex hormone 17β-estradiol (E2) in the male brain and excitatory GABA type A receptor (GABAAR) signaling. We studied whether E2 synthesis and excitatory GABAAR signaling are involved in the mediation of the developmental effects of sevoflurane in male rats.MethodsMale Sprague-Dawley rats were pretreated with the inhibitors of E2 synthesis, formestane, or the Na+-K+-2Cl– (NKCC1) Cl– importer, bumetanide, prior to sevoflurane exposure for 6 h on postnatal (P) day 4, P5, or P6. We tested whether a subsequent exposure of these rats to sevoflurane on P∼10 would cause electroencephalography (EEG)-detectable seizures. We also evaluated their behavior during the elevated plus maze (EPM) test on P∼60, prepulse inhibition (PPI) of acoustic startle responses on P∼70, and corticosterone secretion to physical restraint on P∼80.ResultsThe rats neonatally exposed to sevoflurane responded to repeated exposure to sevoflurane with increased EEG-detectable seizures (F(3,24) = 7.445, P = 0.001) and exhibited deficiencies during the EPM (F(3,55) = 4.397, P = 0.008) and PPI (F(3,110) = 5.222, P = 0.003) tests. They also responded to physical restraint with heightened secretion of corticosterone (F(3,16) = 11.906, P < 0.001). These parameters in the sevoflurane-exposed rats that were pretreated with formestane or bumetanide were not different from those in the control rats.ConclusionThese results, along with previously published data, suggest that sevoflurane-enhanced E2 synthesis and excitatory GABAAR signaling at the time of sevoflurane anesthesia are involved in the mediation of the neurodevelopmental effects of the anesthetic in male rats.

Testosterone (T), predominantly acting through its derivative 17β-estradiol (E2), regulates the brain’s sexual differentiation in rodents during the perinatal sensitive period, which mirrors the window of vulnerability to the adverse effects of general anesthetics. The mechanisms of anesthesia’s adverse effects are poorly understood. We investigated whether sevoflurane alters T and E2 levels and whether they contribute to sevoflurane’s acute adverse effects in postnatal day 5 Sprague-Dawley rats. The rats underwent electroencephalography recordings for 2 h of baseline activity or for 1 h before and another hour during 2.1% sevoflurane exposure, followed by collection of trunk blood and brain tissue. Pharmacological agents, including the GABA type A receptor inhibitor bicuculline and the aromatase inhibitor formestane, were administered 30 min before sevoflurane anesthesia. Sevoflurane increased serum T levels in males only. All other effects of sevoflurane were similar in both sexes, including increases in serum levels of E2, hypothalamic mRNA levels of aromatase, estrogen receptor α (Erα) [not estrogen receptor β (Erβ)], Na+-K+-Cl− cotransporter (Nkcc1)/K+-Cl− cotransporter (Kcc2) mRNA ratio, electroencephalography-detectable seizures, and stress-like corticosterone secretion. Bicuculline and formestane alleviated these effects, except the T level increases. The ERα antagonist MPP, but not the ERβ antagonist PHTPP, reduced electroencephalography-detectable seizures and normalized the Nkcc1/Kcc2 mRNA ratio. Collectively, sevoflurane exacerbates levels of T in males and E2 in both sexes during the period of their organizational effects in rodents. Sevoflurane acts through GABAAR-mediated, systemic T-independent elevation of E2 to cause electroencephalography-detectable seizures, stress-like corticosterone secretion, and changes in the expression of genes critical for brain development.

A combination of antidepressant drugs and psychotherapy exhibits more promising efficacy in treating fear disorders than either treatment alone, but underlying mechanisms of such treatments remain largely unknown. Here we investigated the role of DNA methylation of the brain-derived neurotrophic factor (Bdnf) gene in the therapeutic effects of ketamine in combination with extinction training in a mouse model of post-traumatic stress disorder (PTSD) induced by inescapable electric foot shocks (IFS). Male mice received ketamine for 22 consecutive days starting 1 h after the IFS (long-term ketamine treatment) or 2 h prior to the extinction training on days 15 and 16 after the IFS (short-term ketamine treatment). The Open Field (OF) and Elevated Plus Maze (EPM) tests were conducted on days 18 and 20. The spontaneous recovery and fear renewal tests were performed on day 23. Mice, subjected to IFS, exhibited anxiety-like behavior and fear relapse, accompanied by the increased levels of DNA methyltransferases, hyper-methylation of Bdnf gene, and decreased BDNF mRNA expression in the medial prefrontal cortex (mPFC) and hippocampus (HIP). Long-term treatment with ketamine combined with extinction training alleviated the IFS-induced abnormalities. These results suggest that long-term ketamine treatment in combination with extinction training may ameliorate fear relapse in the murine model of PTSD, at least in part, by normalizing DNA methylation of Bdnf gene.