Isoflurane but Not Halothane Prevents and Reverses Helpless Behavior: A Role for EEG Burst Suppression?

Abstract

BackgroundThe volatile anesthetic isoflurane may exert a rapid and long-lasting antidepressant effect in patients with medication-resistant depression. The mechanism underlying the putative therapeutic actions of the anesthetic have been attributed to its ability to elicit cortical burst suppression, a distinct EEG pattern with features resembling the characteristic changes that occur following electroconvulsive therapy. It is currently unknown whether the antidepressant actions of isoflurane are shared by anesthetics that do not elicit cortical burst suppression.MethodsIn vivo electrophysiological techniques were used to determine the effects of isoflurane and halothane, 2 structurally unrelated volatile anesthetics, on cortical EEG. The effects of anesthesia with either halothane or isoflurane were also compared on stress-induced learned helplessness behavior in rats and mice.ResultsIsoflurane, but not halothane, anesthesia elicited a dose-dependent cortical burst suppression EEG in rats and mice. Two hours of isoflurane, but not halothane, anesthesia reduced the incidence of learned helplessness in rats evaluated 2 weeks following exposure. In mice exhibiting a learned helplessness phenotype, a 1-hour exposure to isoflurane, but not halothane, reversed escape failures 24 hours following burst suppression anesthesia.ConclusionsThese results are consistent with a role for cortical burst suppression in mediating the antidepressant effects of isoflurane. They provide rationale for additional mechanistic studies in relevant animal models as well as a properly controlled clinical evaluation of the therapeutic benefits associated with isoflurane anesthesia in major depressive disorder.

Lack of antidepressant effects of burst-suppressing isoflurane anesthesia in adult male Wistar outbred rats subjected to chronic mild stress

“…The same group subsequently reported similar findings with repeated propofol anesthesia [43]. Moreover, we and others have shown that a single isoflurane anesthesia exposure produces antidepressant-like effects in the learned helplessness depression model and in the forced swim test [44,45], while halothane, another anesthetic agent that produces negligible burst-suppression, lacks such effects [45]. Furthermore, isoflurane activates TrkB receptors in a dose-dependent manner, with the most prominent effects observed when burst-suppression is achieved [35,44].…”

Propofol for Treatment-Resistant Depression: A Pilot Study

“…Substantial clinical evidence now supports the efficacy of ketamine for treatment-resistant depression ( Berman et al, 2000 ; Zarate et al, 2006 ; McGirr et al, 2015 ), and a recent randomized controlled trial demonstrated antidepressant effects of nitrous oxide ( Nagele et al, 2015 ). Several studies have suggested efficacy of another inhaled anesthetic, isoflurane, at high doses in humans ( Langer et al, 1985 , 1995 ; Weeks et al, 2013 ) and rodent models ( Antila et al, 2017 ; Brown et al, 2018 ). Furthermore, positive GABA-A receptor modulators have shown promising antidepressant effects ( Kanes et al, 2017 ; McMurray et al, 2018 ).…”

TrkB neurotrophin receptor at the core of antidepressant effects, but how?

“…Remarkably, a single and brief isoflurane anesthesia produced antidepressant-like behavioral responses and facilitation of LTP several hours or a day later after the treatment (Antila et al 2017). Antidepressant-like behavioral effects of isoflurane have been recently reported also by others (Brown et al 2018). Similarly with the classical antidepressants, isoflurane regulates TrkB activation also in Bdnfdeficient mice (Antila et al 2017) and the effects seem restricted to adult animals (Rantamäki et al, unpublished).…”

“…Similarly with the classical antidepressants, isoflurane regulates TrkB activation also in Bdnfdeficient mice (Antila et al 2017) and the effects seem restricted to adult animals (Rantamäki et al, unpublished). Halothane, a closely related volatile anesthetic, is reported to have no antidepressant-like effects (Brown et al 2018), although it does regulate TrkB signaling at anesthetic doses (Antila et al 2017). It should be noted that of all the tested pharmacological manipulations so far, deep anesthesia is clearly one of the most potent and reliable means of inducing TrkB phosphorylation in the adult rodent brain (Theilmann et al 2019).…”