Isoflurane produces antidepressant effects and induces TrkB signaling in rodents

Abstract

A brief burst-suppressing isoflurane anesthesia has been shown to rapidly alleviate symptoms of depression in a subset of patients, but the neurobiological basis of these observations remains obscure. We show that a single isoflurane anesthesia produces antidepressant-like behavioural effects in the learned helplessness paradigm and regulates molecular events implicated in the mechanism of action of rapid-acting antidepressant ketamine: activation of brain-derived neurotrophic factor (BDNF) receptor TrkB, facilitation of mammalian target of rapamycin (mTOR) signaling pathway and inhibition of glycogen synthase kinase 3β (GSK3β). Moreover, isoflurane affected neuronal plasticity by facilitating long-term potentiation in the hippocampus. We also found that isoflurane increased activity of the parvalbumin interneurons, and facilitated GABAergic transmission in wild type mice but not in transgenic mice with reduced TrkB expression in parvalbumin interneurons. Our findings strengthen the role of TrkB signaling in the antidepressant responses and encourage further evaluation of isoflurane as a rapid-acting antidepressant devoid of the psychotomimetic effects and abuse potential of ketamine.

Effects of the presence and absence of amino acids on translation, signaling, and long‐term depression in hippocampal slices from Fmr1 knockout mice

“…Our study of the effects of propofol anesthesia on PS rates measured in vivo indicated that Fmr1 KO, but not WT, mice responded to propofol anesthesia with altered rates of overall PS (Qin et al ). Moreover, work of others has shown lasting effects of quickly cleared anesthetics such as isoflurane and halothane in WT mice on the activation of proteins such as ERK, mTOR, eIF2α, and p70S6K (Palmer et al ; Qin et al ; Antila et al ; Kang et al ). These proteins are involved in the regulation of PS and are thought to be involved in the group 1 mGluR response.…”

Convergent Mechanisms Underlying Rapid Antidepressant Action

“…Ketamine and other putative rapid antidepressant drugs also increase the phosphorylation (activation) of hippocampal and/or mPFC TrkB [43, 198, 298], suggesting a BDNF-TrkB-dependent mechanism of rapid antidepressant action. Notably, there is also evidence that isoflurane, an anesthetic drug, may possess relatively rapid antidepressant actions in treatment-resistant patients [323–325] and antidepressant behavioral responses in the learned helplessness and the novelty-suppressed feeding tests in rodents [326], plausible via a TrkB-dependent mechanism [326]. Further studies are required to assess for additional mechanisms whereby rapid and/or sustained antidepressant actions of isoflurane exposure may converge with other rapid-acting antidepressants.…”

Putative rapid-acting antidepressant nitrous oxide (“laughing gas”) evokes rebound emergence of slow EEG oscillations during which TrkB signaling is induced

“…Animals were sacrificed at indicated times after the treatments by rapid cervical dislocation followed by de-capitation. No anesthesia was used due to its potential confounding effects on the analyses 22 . Bilateral medial prefrontal cortex (including prelimbic and infralimbic cortices) was rapidly dissected on a cooled dish and stored at -80 °C 22,23 .…”

“…Sample protein concentrations were measured using Bio-Rad DC protein assay (Bio-Rad Laboratories, Hercules, CA). Proteins (40-50 μg) were separated with SDS-PAGE under reducing and denaturing conditions and blotted to a PVDF membrane as described 22,23 . Membranes were incubated with the following primary antibodies (see Ref.…”

“…Membranes were incubated with the following primary antibodies (see Ref. 22 ): anti-p-TrkB (#4168; 1:1000; Cell signaling technology (CST)), anti-TrkB (1:1000; #4603, CST), anti-Trk (sc-11; 1:1000; Santa Cruz Biotechnology (SCB); ), antip-CREB (#9191S; 1:1000; CST), anti-p-p70S6K (#9204S; 1:1000; CST), anti-p-GSK3βS9 (#9336; 1:1000; CST), antip-p44/42-MAPK Thr202/Y204 (#9106, 1:1000, CST), anti-GSK3β (#9315, 1:1000, CST), anti-p70S6K (#2708, 1:1000, CST) anti-p44/42-MAPK (#9102, 1:1000, CST) and anti-GAPDH (#2118, 1:10 000, CST). Further, the membranes were washed with TBS/0.1% Tween (TBST) and incubated with horseradish peroxidase conjugated secondary antibodies (1:10000 in non-fat dry milk, 1 h at room temperature; Bio-Rad).…”