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

Abstract

Background: The 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.

Methods: In 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.

Results: Isoflurane, 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.

Conclusions: These 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.

Keywords: electroconvulsive therapy; fast-acting antidepressant; halothane; learned helplessness; treatment-resistant depression.

Figure 1.

Isoflurane (ISO) but not halothane (HALO) elicits cortical burst suppression in rodents. (A) Representative tracing illustrating burst suppression EEG pattern in a rat anesthetized with ISO (2.5%). Switching from ISO to HALO (arrow) results in a short latency cessation in burst suppression and the emergence of a high-voltage continuous slow wave EEG pattern characteristic of HALO anesthesia. (B) Dose-response curve illustrating the relationship between burst suppression ratio (BSR, left ordinate) and duration of the postburst suppression (right ordinate) as a function of ISO concentration. Each point represents the mean±SEM obtained from 4 to 6 rats. (C) Representative EEG recordings illustrating the effects of increasing concentrations of ISO (left) and HALO (right) on EEG activity in CD-1 mice. (D) Dose-response curve describing the relationship between BSR (left ordinate) and duration of the postburst suppression (right ordinate) as a function of ISO concentration. Each point represents the mean±SEM obtained from 6 mice.

Figure 2.

Prior exposure to isoflurane (ISO) but not halothane (HALO) reduces the incidence of learned helplessness in Sprague-Dawley rats. (A) Procedural summary and timeline. (B) Bar graph illustrating the average (mean±SEM) number of escape failures (30 trials total) in untreated rats (n=10) and rats that had been previously anesthetized with HALO (1.5%) for 2 hours (n=12). (C) Line plot illustrating the average number of escape failures (mean±SEM) among naïve controls and HALO-treated rats in blocks of 5 trials for the duration of the test session on Day 2. (D) Bar graph illustrating the average (mean±SEM) number of escape failures in untreated rats (n=12) and rats that had been previously anesthetized with ISO (2%) for 2 hours (n=12). (E) Line plot illustrating the average number of escape failures (mean±SEM) for control and ISO-treated rats in blocks of 5 trials for the duration of the test session (Day2).

Figure 3.

Exposure to isoflurane (ISO) but not halothane (HALO) 24 hours prior to testing reverses helpless behavior in CD-1 mice. (A) Procedural summary and timeline. (B) Bar graph illustrating the average number of escape failures (45 trials total) in untreated helpless mice (n=13) and helpless mice that been anesthetized with HALO (2.0%, n=12) or ISO (2.5%, n=13). (C) Line plot illustrating the average number of escape failures for control, HALO-treated, and ISO-treated in blocks of 5 trials for the duration of the retest session (Day 4). Data are the mean±SEM.