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: learned helplessness, treatment-resistant depression, halothane, electroconvulsive therapy, fast-acting antidepressant Introduction Major depressive disorder is a disabling and life-threatening with this disorder respond to conventional antidepressant disease with a lifetime prevalence of 17% in the US population medications, only one-half to one-third achieve full remis- (Kessler et al., 2003). While 50% to 70% of patients diagnosed sion (Olchanski et al., 2013). Upwards of 30% of patients with Received: January 15, 2018; Revised: March 4, 2018; Accepted: March 14, 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, 1 provided the original work is properly cited. For commercial re-use, please contact firstname.lastname@example.org Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy029/4938364 by Ed 'DeepDyve' Gillespie user on 08 June 2018 2 | International Journal of Neuropsychopharmacology, 2018 Significance Statement Preliminary clinical trials have suggested that isoflurane anesthesia is as effective as electroconvulsive therapy in medication- resistant depression. Both treatments produce a temporary suppression in electroencephalographic activity that could be func- tionally linked to their therapeutic effects. Recently, it was shown that isoflurane and another volatile anesthetic, halothane, activate TrkB receptors, implying that isoflurane and the rapidly acting antidepressant ketamine share a common mechanism of action. Here we show that isoflurane, in contrast to halothane, induces burst suppression in cortical electroencephalographic activity. Isoflurane, but not halothane, also reverses helpless behavior in mice and prevents its development in rats. These results provide rationale for additional mechanistic studies in animal models and a definitive evaluation of the potential therapeutic benefits of isoflurane anesthesia in major depressive disorder. In addition to providing an alternative treatment strategy for patients, these studies may converge on mechanisms that provide an explicit functional link between burst suppression anes- thesia and electroconvulsive therapy. medication-resistant depression, defined as the failure to achieve to produce EEG burst suppression. The results indicate that full remission with an adequate dose and duration of treatment ISO, but not HALO anesthesia, prevents the development and (Fava, 2003), also fail to achieve remission after 4 sequential trials reverses learned helplessness. These findings provide additional with different antidepressant medications. This type of chronic support for the efficacy of ISO as a rapidly-acting antidepressant medication-resistant depression is associated with persistent and suggest the involvement of burst suppression as the rele- vocational disability, substantially higher risk of suicide, and sig- vant mechanism underlying these effects. nificantly higher health care utilization costs (Russell et al., 2004; Dunner et al., 2006; Olchanski et al., 2013). Methods Electroconvulsive therapy (ECT) is an effective treatment for medication-resistant depression (Kellner et al., 2012). ECT Animals induces a generalized tonic-clonic seizure characterized by par - oxysmal EEG discharges followed by the abrupt onset of a flat Adult male Sprague-Dawley rats (n = 46) and adult male CD1 (i.e., isoelectric) EEG referred to as postictal suppression. Efforts mice (n = 101) obtained from Charles River were maintained on a to associate specific EEG changes with treatment response have 12-hour-light/-dark cycle and provided ad libitum access to food implicated the duration of postictal suppression as a deter - and water. All experiments and procedures were conducted in minant of clinical outcome following ECT (Krystal et al., 1993; strict accordance with recommendations in The Guide for the Suppes et al., 1996; Perera et al., 2004; Azuma et al., 2007, 2010; Care and Use of Laboratory Animals of the National Institutes of Kranaster et al., 2013). Support for the role of cortical isoelectric- Health (2011) and the University of Maryland School of Medicine ity in the mechanism of action of ECT was obtained from early Institutional Animal Care and Use Committee. clinical studies comparing its efficacy with repeated isoflurane (ISO) treatments. Like ECT, deep anesthesia with ISO elicits dis- EEG Recording tinctive EEG changes characterized by brief, high-amplitude, low-frequency bursts followed by prolonged intervals of elec- Anesthesia was induced in rats (n= 6) and mice (n = 12) with trical suppression. Several preliminary clinical trials found that HALO or ISO (3% in 100% O , 1 Liter/min) in a ventilated induction repeated ISO anesthesia to EEG burst suppression is as effective chamber, and the animals were mounted in a stereotaxic instru- as ECT in reducing symptoms in patients with major depressive ment equipped with a nose cone from which additional anes- disorder (Langer et al., 19851995 , ; Carl et al., 1988; Engelhardt thetic was delivered using precision vaporizers (HALO, Ohmeda et al., 1993; Weeks et al., 2013) without producing the deleteri- Fluotech 4; ISO, VetEquip). Body temperature was monitored con- ous side effects typically associated with ECT (Carl et al., 1988; tinuously and maintained at 36°C using a feedback-controlled Weeks et al., 2013). However, 2 groups reporting limited bene- heating pad. The scalp was incised and 2 small burr holes drilled fit of burst suppression anesthesia in patients (Greenberg et al., in the skull overlying the frontal cortex. A pair of stainless-steel 1987; García-Toro et al., 20012004 , ) along with the lack of pre- (SNEX, Rhodes Medical Equipment) or Ag/AgCl pellet electrodes clinical data supporting a role for ISO anesthesia in animal mod- (Warner Instruments) were positioned on the surface of the cor - els of MDD stalled interest in this potential treatment. tex and submerged in mineral oil. EEG was recorded between Recently, Antila and colleagues (2017) reported that a sin- the left and right hemispheres using a differential amplifier gle exposure to ISO anesthesia prevented the development of (DAM-80, World Precision Instruments), filtered (1–100 Hz band- learned helplessness in rats, an established model of depres- pass), and digitized at 1 KHz using a 16-bit laboratory interface sion-related maladaptive behavior (Maier and Seligman, 2016). (Digidata 1321A; Molecular Devices). During the recording, ISO or The antidepressant-like effects of ISO were accompanied by acti- HALO concentration was increased in a stepwise fashion. After vation of the brain-derived neurotropic factor receptor, TrkB, an obtaining the response to the highest dose of the first anesthetic effect implicated in the mechanism of action of the rapid-acting administered, animals were switched to an equivalent concen- antidepressant, ketamine (Li et al., 2010A ; utry et al., 2011; Liu tration of the alternate anesthetic and recordings continued for et al., 2012). Notably, halothane (HALO), a structurally unrelated an additional 10 to 15 minutes. Cortical EEG was acquired con- volatile anesthetic, was found to induce comparable changes in tinuously during the experiment and recorded for offline ana- TrkB signaling, suggesting that it may share ISO’s antidepressant lysis using Spike 2 (CED). The burst suppression ratio (BSR) was actions (Antila et al., 2017). To test this hypothesis, we compared computed using a thresholding algorithm that determined the the effects of ISO and HALO anesthesia on learned helplessness time of occurrence and the duration of each burst in the EEG rec- in rats and mice. The doses used were comparable with those ord. The interval between consecutive burst starts was taken as previously shown to activate TrkB but differed in their ability the event duration and the BSR computed as follows: Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy029/4938364 by Ed 'DeepDyve' Gillespie user on 08 June 2018 Brown et al. | 3 adaptation period, 120 inescapable foot-shocks (0.45 mA, 15-sec- EventDuration- Burstduration BSR= 100. ond duration, randomized 45-second average, range 40–50 sec- EventDuration ond inter-shock interval) were delivered through a grid-floor. Following the session, mice were returned to their home cage. Learned Helplessness in Rats The following day (Day 2 to screening), mice were placed in one of the 2 compartments of the apparatus for a 5-min period and Rats were individually housed and assigned to 1 of 3 treatment immediately after a 3-second foot-shock (0.45 mA) was deliv- groups including ISO (n= 12), HALO (n = 12), or control (CON, ered, and the door between the 2 chambers was raised simul- n = 22). Animals in the ISO and HALO groups were induced with taneously. Crossing over into the second chamber terminated isoflurane (3%) or halothane (3%), respectively, in 100% O (1 l/ the shock. If the animal did not cross over, the shock terminated min) using a ventilated induction chamber. Once unconscious, after 3 seconds. A total of 30 screening trials of escapable shocks rats were placed in a stereotaxic instrument using atraumatic was presented to each mouse with an average of 30 seconds earbars, and a nosecone was used to deliver either ISO (2%) or (range 25–35 seconds) delay between each trial. HALO (1.5%) continuously for 2 hours. A feedback-controlled On Day 3 (treatment) mice that developed helplessness heating pad was used to maintain body temperature at 36°C. behavior (>20 total escape failures and >5 escape failures during Following anesthesia exposure, rats recovered on a warm heat- the last 10 screening shocks) received the assigned treatment ing pad until ambulatory at which point they were returned to (controls: no exposure, 2.0% HALO for 1 hour, or 2.5% ISO for 1 their home cages. CON rats were brought to the surgery room hour) 24 hours following screening. Control mice remained in and returned to the animal quarters 2 hours later without hav- their home cages while mice in the ISO and HALO groups were ing received either anesthetic. induced individually with their respective anesthetics and sub- Two weeks following the initial treatment, all rats under - sequently transferred to a divided and ventilated holding cham- went a modified 2-day learned helplessness procedure based ber (4 mice/chamber) maintained at 37°C where they continued on previously published studies in the rat (Vollmayr and Henn, to receive their respective anesthetic for a total of 1 hour. Mice 2001; Shirayama et al., 2002). On Day 1, individual animals were were allowed to recover from the effects of the anesthesia in placed on one side of a 2-chamber shuttle-box (21 × 21 × 16 cm; individual cages before they were returned to their home cage. Med Associates) configured to deliver scrambled electric shocks During the LH test phase (Day 4), the animals were placed on to metal floor bars. The chamber was equipped with 4 pairs of one side of the shuttle box and after a 5-minute adaptation parallel horizontal infrared photobeams positioned 12 cm apart period, a 0.45-mA shock was delivered concomitantly with and 3 cm above the grid floor. Following a brief acclimation the door opening for the first 5 trials. For the next 40 trials, the period, the rats received a total of 120 shocks (0.8 mA) of vari- shock was delivered for 2 seconds prior to opening the door. able duration (5–15 seconds) applied at random intervals (5–15 Crossing over to the second chamber terminated the shock. If seconds) during a 40-minute session. At the end of the session, the animal did not cross over to the other chamber, the shock all rats were returned to their home cages and the shuttle box was terminated after 24 seconds. A total of 45 trials of escapable wiped clean with 70% ethanol. shocks was presented to each mouse with 30-second inter-trial The following day, rats were returned to the same chamber intervals. The number of escape failures was recorded for each used on Day 1 where they received an additional 30 inescapable mouse by automated computer software (Graphic State v3.1; foot-shocks using the stimulus parameters described above. Coulbourn Instruments). Following the last shock, the house lights came on initiating a new set of 30 trials that began with a 5-second tone signaling Statistical Analysis the opening of a guillotine door (9 cm wide by 11 cm high) sep- arating the 2 compartments. At the termination of the tone, a All data are expressed as the mean ± SEM. Sample sizes were scrambled electrical shock (0.8 mA) was applied to the floor grid estimated from previous studies using similar techniques and for a maximum of 15 seconds. Crossing to the opposite, non- animals were randomly assigned to their respective treatment electrified side of the chamber and breaking the far photobeam groups. All statistical analyses were conducted in SigmaPlot at any point during the shock triggered closure of the guillotine ν.12.5 (Systat Software). Omnibus testing was conducted using door and termination of the trial which was scored as an escape. a 1- or 2-way ANOVA unless the underlying assumptions of nor - Crossing to the nonelectrified side of the box in response to the mality and/or equal variance were violated, in which case the predictive tone and thus prior to shock delivery rarely occurred Kruskal–Wallis 1-way ANOVA on ranks was substituted. but was scored as an avoidance response. Failure to escape the shock within the 15-second interval terminated the trial, which Results was scored as an escape failure. Differential Effects of Halothane and Isoflurane on Learned Helplessness in Mice Cortical EEG On arrival, mice were housed in groups of 5 animals per cage. EEG recordings obtained from Sprague-Dawley rats anesthe- Consistent with previously published reports (Zanos et al., tized with ISO exhibited pronounced burst suppression consist- 2016), the learned helplessness procedure consisted of 4 phases: ing of an initial burst of high-amplitude activity followed by a inescapable shock training, screening, treatment, and test. To prolonged interval of electrical quiescence (Figure 1A). At the avoid disrupting their social environment, mice were housed lowest concentration tested (1.5%), the duration of the burst with their original cage-mates throughout all phases of the and the subsequent interval of isoelectric activity were equiva- experiment. For the inescapable shock training phase (Day 1 lent, yielding a BSR of ~50%. Increasing the concentration of to induction), mice were placed in one side of a 2-chambered ISO resulted in a dose-dependent increase in BSR (Figure 1B , shuttle box (34× 37 × 18 cm; Coulbourn Instruments). A door F = 7.3, P < .01) that ranged from 69% to 82% at the highest (2,12) separating the chambers remained closed. Following a 5-minute concentration tested (2.5%). Although a small reduction in burst Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy029/4938364 by Ed 'DeepDyve' Gillespie user on 08 June 2018 4 | International Journal of Neuropsychopharmacology, 2018 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. duration typically occurred at higher concentrations, the dose- 2 cohorts of animals were pretreated with ISO (2.0%) or HALO dependent increase in BSR under ISO was largely attributable to (1.5%) for 2 hours prior to being returned to their home cage. an increase in the duration of the postburst suppression in EEG The concentrations of ISO and HALO were adjusted to account activity (Figure 1B , H = 7.7, P < .05), which at the highest concen- for differences in their respective potencies (Mazze et al., 1985) (2) tration tested ranged from 7 to 41 seconds. By contrast, HALO while maximizing the burst suppression effects of ISO. Two sep- did not elicit EEG burst suppression at any of the concentrations arate groups of rats served as controls and were not treated with tested (up to 3%; the highest dose that did not induce respiratory any drug. Two weeks later, all rats entered a 2-day learned help- depression) even after a prolonged exposure to ISO (Figure 1A). lessness procedure consisting of repeated exposure to an unpre- We also recorded cortical EEG in CD-1 mice exposed to dictable and uncontrollable foot-shock followed 24 hours later increasing concentrations of both anesthetics. As anticipated, by 30 trials in which subjects could avoid or escape the stressor ISO anesthesia was associated with a burst suppression EEG (Figure 2A). As illustrated in Figure 2B and C, the number of rats pattern qualitatively similar to that observed in rats (Figure 1C, that failed to escape the shock when provided the opportunity left panel). The BSR increased as a function of ISO dose to do so did not differ between controls and rats that had been (Figure 1D, F = 15.0, P < .001). As in rats, burst duration tended previously exposed to HALO anesthesia (F = 0.041, P = .842). By (4,25) (1,20) to decrease with increasing doses of ISO (1% ISO: 1.6 ± 0.16 s, 2% contrast, rats pretreated with ISO exhibited fewer escape fail- ISO: 1.0 ± 0.19 s), but these differences did not reach statistical ures overall compared with their naïve counterparts (F = 5.88, (1,22) significance (F = 2.4, P = .08). However, the duration of the post- P = .024; Figure 2D). A significant main effect for trial block was (4,25) burst isoelectric interval increased significantly as a function of also observed with rats exhibiting fewer escape failures as the ISO concentration (Figure 1D; F = 5.04, P < .005). As illustrated session progressed (F = 2.580, P = .030; Figure 2E). There was (4,25) (5,110) in Figure 1C (right panel), HALO failed to induce burst suppres- no significant interaction between treatment and trial block. sion at any of the concentrations tested. Isoflurane Reverses Learned Helplessness in Isoflurane Prevents the Development of Learned CD-1 Mice Helplessness in Rats ISO and HALO were also evaluated for their ability to reverse To determine whether prior exposure to burst suppression anes- learned helplessness in animals prescreened for expression of thesia prevents the expression of learned helplessness in rats, this maladaptive behavior. In an effort to increase throughput Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy029/4938364 by Ed 'DeepDyve' Gillespie user on 08 June 2018 Brown et al. | 5 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) n umber of escape failures (30 trials total) in untreated rats (n = 10) and r ats 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 naï ve 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) n umber 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). and to extend our earlier findings to include another species, treatment condition (F = 5.14, P = .01) with mice exposed to (2,35) these studies were conducted using CD-1 mice. A total of 89 ISO showing significantly fewer escape failures than controls or mice were trained (Day 1) and subsequently screened (Day HALO-treated mice. 2) in a modified learned helplessness paradigm (Figure 3A and Methods). Of these, 38 mice reached criteria for helpless behav- Discussion ior and were randomly assigned to 1 of 3 treatment groups including cage control (n = 13), ISO (n = 13), or HALO (n = 12). Prior The results of the present study demonstrate that acute admin- to treatment, the average number of escape failures exhibited istration of ISO, in doses that produce cortical burst suppression, by mice in each group was nearly identical (CON: 27.15 ± 0.77; exerts an antidepressant-like effect in the learned helplessness HALO: 26.75 ± 0.98; ISO: 27.15 ± 0.74). Twenty-four hours after paradigm, a canonical animal model of a depression phenotype screening, mice were induced and exposed to 1 hour of continu- (Maier and Seligman, 2016). In mice exhibiting helpless behav- ous administration of HALO (2.0%) or ISO (2.5%). The concentra- ior, a single, 1-hour exposure to ISO reduced escape failures tion of ISO and HALO were adjusted to account for differences within 24 hours of the initial treatment. The rapid onset of these in potency while maximizing the burst suppression effects of effects following only a single exposure are consistent with ISO. Control mice were transported to the treatment room but those of the fast-acting antidepressant ketamine (Maeng et al., remained in their home cages for the duration of the anesthetic 2008; Zanos et al., 2015, 2016). Relative to the effects of conven- treatment. On the following day, all mice exhibiting the help- tional antidepressant drugs (e.g., fluoxetine), which do not exert less phenotype were tested to determine the effects of prior effects following a single administration in our mouse learned anesthetic exposure on the number of escape failures. As illus- helplessness paradigm (Zanos et al., 2015), both ketamine and trated in Figure 3B , a significant main effect was observed for ISO are effective within 24 hours after a single administration. Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy029/4938364 by Ed 'DeepDyve' Gillespie user on 08 June 2018 6 | International Journal of Neuropsychopharmacology, 2018 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. In rats, prior exposure to 2 hours of ISO reduced the incidence and mice (Kharasch et al., 1999Martignoni et ; al., 2006). To the best of a depression-related maladaptive behavior (failure to escape of our knowledge, this study is the first to directly compare anes- an electric shock) 2 weeks following treatment, indicating that thetic agents that differ in their ability to elicit EEG burst suppres- ISO’s effects are potentially long lasting. Consistent with this, in sion on a depression-related phenotype in animals. rats, a single, brief (30-minute) ISO anesthesia administered 24 Volatile anesthetics including ISO and HALO interact with hours following inescapable shock reduced the number of sub- a host of CNS targets and have the potential to alter neuronal sequent escape failures in the learned helplessness paradigm activity in a variety of ways. Thus, it is not certain whether the 6 days after administration (Antila et al., 2017). ISO was also observed differences in the antidepressant effects of ISO and found to exhibit antidepressant actions in mice evaluated using HALO are completely attributable to their differential effects the tail suspension and novelty suppressed feeding paradigms on cortical EEG. However, despite their structural differences, 15 to 30 minutes after administration (Antila et al., 2017); how- both drugs exhibit a remarkably similar pharmacodynamic pro- ever, see also (Yonezaki et al., 2015). file and do not differ substantially in their ability to modulate a Studies in humans have proposed that EEG burst suppres- number of ligand-gated ion channels in the CNS. ISO and HALO sion is required for ISO to exert its antidepressant therapeutic are both potent positive allosteric modulators of GAB , A gly- effects (Langer et al., 1995); however, this hypothesis cannot be cine, 5-HT , and kainate receptors and are equally effective as tested directly in clinical trials. Here, we used an animal model to negative modulators of nicotinic acetylcholine and AMPA recep- assess the effects of 2 volatile anesthetics, with markedly differ - tors (Krasowski and Harrison, 1999). Similarly, both anesthetics ent effects on cortical activity on a depression-related behavioral only modestly attenuate NMDA receptor activity (Krasowski phenotype. EEG recordings established the ability of ISO to elicit and Harrison, 1999). ISO and HALO also share similar poten- sustained burst suppression in both rats and mice (Murrell et al., cies as activators of 2-pore domain K channels, including TASK 2008; Land et al., 2012). These effects were strongly dose depend- and TREK-1 (Patel et al., 1999; Luethy et al., 2017), a family of ent and largely attributable to an increase in the duration of the ion channels implicated in the mechanism of action of vola- postburst suppression (Hartikainen et al., 1995 Land et ; al., 2012). tile anesthetics. In addition, both act as inhibitors of inwardly Here we show that HALO fails to induce burst suppression in rats rectifying K channels (Sirois et al., 1998) and voltage-gated or mice at any of the concentrations evaluated. HALO anesthe- Na currents, which are inhibited in proportion to anesthetic sia also had no effect on learned helplessness paradigm in either potency (Ouyang et al., 2009). Of particular note Antila et , al. rats or mice. These differences are unlikely to reflect a disparity in (2017) recently attributed the antidepressant-like behavioral the degree of anesthesia, since the doses used in the behavioral effects of ISO in rodents to an increase in TrkB signaling among studies were adjusted to account for the differences in anesthetic parvalbumin interneurons. However, these authors and others potency between ISO and HALO (Mazze et al., 1985Kr ; asowski and (Kang et al., 2017) have shown that both HALO and ISO increase Harrison, 1999) and the known metabolic differences between rats TrkB signaling, implying both anesthetics should exhibit similar Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy029/4938364 by Ed 'DeepDyve' Gillespie user on 08 June 2018 Brown et al. | 7 antidepressant effects in rodents—a prediction that is not sup- Statement of Interest ported by our findings. Dr Shepard has received consulting fees from Takeda In contrast to their reciprocal effects on a number of sig- Pharmaceuticals U.S.A., Inc. and Eli Lilly and Company dur - nal transduction mechanisms, ISO and HALO exert different ing the preceding 3 years. Dr Gould has received consulting effects on brain metabolism and cellular energetics. At clin- fees from Janssen Pharmaceuticals and research funding from ically relevant doses, ISO and HALO have disparate effects on Janssen Pharmaceuticals and Roche Pharmaceuticals during the the cerebral metabolic rate of oxygen (CMR) ( OAlgotsson et al., preceding 3 years. All other authors report no financial interest 1988; Kuroda et al., 1996), differences that may account for the to disclose. pronounced dissimilarity in their effects on cortical EEG (Ching et al., 2012; S. Liu and Ching, 2017). Burst suppression, identi- cal to that associated with ISO anesthesia, occurs under a -var References iety of conditions associated with depressed CMRO including hypothermia (Stecker et al., 2001Madhok ; et al., 2012; Chen Algotsson L, Messeter K, Nordström CH, Ryding E (1988) Cerebral et al., 2013) and hypoxic coma (Hofmeijer and van Putten, 2016). blood flow and oxygen consumption during isoflurane and The mechanism(s) responsible for the generation of cortical halothane anesthesia in man. Acta Anaesthesiol Scand burst suppression are incompletely understood but appear to 32:15–20. involve both intrinsic cellular and corticothalamic network Amzica F, Kroeger D (2011) Cellular mechanisms underlying EEG properties (Amzica and Kroeger, 2011). The process responsible waveforms during coma. Epilepsia 52:25–27. for the transition from bursting to isoelectric suppression is Antila H, et al. (2017) Isoflurane produces antidepressant effects of particular relevance given that the therapeutic effects of and induces TrkB signaling in rodents. Sci Rep 7:7811. ECT are related to the duration of postictal suppression, the Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, Kavalali EEG “congener” of ISO-induced postburst isoelectricity. It has ET, Monteggia LM (2011) NMDA receptor blockade at rest trig- been suggested that the transition from burst to isoelectric gers rapid behavioural antidepressant responses. Nature 2+ quiescence is mediated by a Ca -induced increase in synaptic 475:91–95. transmission or a reduction in neuronal excitability resulting Azuma H, Fujita A, Sato K, Arahata K, Otsuki K, Hori M, Mochida from enhanced charge screening at Na channels (Kroeger and Y, Uchida M, Yamada T, Akechi T, Furukawa TA (2007) Postictal Amzica, 2007). More recently, Ching et al. (2012) suggested that suppression correlates with therapeutic efficacy for depres- bursts transiently deplete intracellular ATP levels, leading to sion in bilateral sine and pulse wave electroconvulsive ther - an increase in the activity of ATP-gated K channels. A compu- apy. Psychiatry Clin Neurosci 61:168–173. tational model based on this notion recapitulates burst sup- Azuma H, Yamada A, Shinagawa Y, Nakano Y, Watanabe N, pression morphology and faithfully predicts the membrane Akechi T, Furukawa TA (2011) Ictal physiological character - hyperpolarization and increase in pyramidal cell conductance istics of remitters during bilateral electroconvulsive therapy. that occurs during the isoelectric phase of burst suppres- Psychiatry Res 185:462–464. sion (Steriade et al., 1994). 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International Journal of Neuropsychopharmacology – Oxford University Press
Published: Mar 15, 2018
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