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Exploratory analyses of postanesthetic effects of desflurane using behavioral test battery of mice

Niikura, Ryoa,,*; Miyazaki, Tomoyukia,,b,,*; Yonezaki, Kumikoa,,*; Uchimoto, Kazuhiroa; Takase, Kenkichic; Goto, Takahisaa

Author Information
doi: 10.1097/FBP.0000000000000567

Abstract

Introduction

Halogenated ethers, such as desflurane, sevoflurane, and isoflurane, are the major anesthetic agents used in clinical and experimental settings. These anesthetics induce sedation by acting on the GABAA receptor, the NMDA receptor, voltage-gated potassium channels, muscarinic acetylcholine receptors, and two-pore potassium channels, and differentially affect some other receptors including kainate receptors, the glycine receptor, nicotinic acetylcholine receptors, serotonin receptors, and the AMPA receptor (Rudolph and Antkowiak, 2004; Alkire et al., 2008; Franks, 2008). The widespread and diverse sites of action of each agent determine an array of effects of these anesthetics besides their anesthetic action. Some of the molecules targeted by these anesthetics are essential for the maintenance of neuronal homeostasis. Once neurons lose their homeostasis, the sequential disruption of neural circuits causes a variety of prolonged side effects (i.e. postanesthetic effects) in addition to acute side effects. The postanesthetic effects of halogenated ethers on the developing brain have been investigated extensively in neonatal animals (Lin et al., 2017), but remain elusive in adult animals.

We previously reported that isoflurane has postanesthetic effects in adult animals. Isoflurane impairs learning performance by hindering neural-based causal changes in rats (Uchimoto et al., 2014). Moreover, our previous study revealed, using comprehensive behavioral test batteries, that mice exposed to 1.8% isoflurane for 2 h exhibit attention deficits 7 days after anesthesia (Yonezaki et al., 2015). Halogenated ethers share their sites of actions (Rudolph and Antkowiak, 2004; Alkire et al., 2008; Franks, 2008), and thus we hypothesized that also desflurane, like isoflurane, could have postanesthetic effects on adult behavioral phenotypes.

As desflurane is frequently used in clinical settings, investigating a wide array of postanesthetic behavioral effects is potentially important for the prevention of postoperative behavioral dysfunction. However, only three studies have examined the postanesthetic effects of desflurane on behavior of adult rodents (Kilicaslan et al., 2013; Tang et al., 2013; Callaway et al., 2015). Moreover, all of three studies only evaluated postanesthetic effects on spatial learning and memory using the same task, Morris water maze. Callaway et al. (2015) demonstrated that 4-h exposure to 1.5 minimum alveolar concentration (MAC), but not 1.0 MAC, desflurane retarded spatial learning speed of Morris water maze performed at 7 days after anesthesia in aged (20–24 months old) rats, whereas their acquisition and retention of spatial memory was intact. In this study, both 1.0 and 1.5 MAC desflurane did not affect spatial learning and memory in young (3 months old) rats. Tang et al. (2013) demonstrated that 30-minute exposure to 9.0% desflurane did not affect spatial learning speed, acquisition and retention memory of Morris water maze performed at 1 and 14 weeks after anesthesia in 5–11 months old mice. Kilicaslan et al. (2013) demonstrated that acute (4 h) and chronic (2 h × 5 days) exposure to 7.8% desflurane did not affect spatial learning speed, acquisition and retention memory of Morris water maze performed at 24 h after anesthesia in 2 months old mice. Since desflurane has widespread and diverse sites of action, we thought that the postanesthetic effect of this agent need to be evaluated in multifaceted and diversified manner. Therefore, in the current study, we behaviorally phenotyped desflurane-treated mice to systematically investigate its postanesthetic effects on general health, fundamental behavior, and higher behavioral functions of mice.

Methods

Subjects

In total, 145 male C57BL/6J mice (weight 19–27 g, 6 weeks old) were obtained from Japan SLC, Inc. (Tokyo, Japan). The animals were maintained in a temperature-controlled room (23 ± 2°C) with a 14–10 h light-dark cycle (light period, 5:00–19:00) and provided with food and water ad libitum. All experiments were carried out in strict accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals of the Yokohama City University. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Yokohama City University (Permit Number: F-A-13-049).

General anesthesia exposure

One week after the mice arrived at the laboratory, desflurane exposure was performed according to the method of Yonezaki et al. (2015). Mice undergoing general anesthesia were placed in a translucent plastic chamber (25 × 17.5 × 8 cm) within a thermostatic bath (34 ± 2°C). The chamber was provided with oxygen and nitrogen (FiO2 = 0.33) at 6 L/min. Rectal temperature was monitored and maintained at 36.5 ± 0.5°C. The concentration of desflurane was maintained 8.0% for 6 h, corresponding to 1.3 MAC. This concentration corresponds to the 1.8% isoflurane in our previous study (Yonezaki et al., 2015). The carbon dioxide in the chamber was maintained below 3 mmHg. The gases were monitored using a Capnomac ULTIMA monitor (Datex, Helsinki, Finland). In the control group, one mouse at a time was placed in a plastic chamber flushed with the same carrier gas for 5 minutes and then returned to its original cage. The concentration of 1.3 MAC is a relatively high concentration used in clinical setting. Desflurane is rarely used above 1.5 MAC because it exhibits respiratory tract irritation and impaired cerebral autoregulation at 1.5 MAC and above (Strebel et al., 1995), as well as increment in arterial blood pressure and heart rate (Ebert et al., 1995). Moreover, desflurane has lower solubility in blood and other body tissues, and has lower metabolism as compared with other inhaled halogenated anesthetics, indicating that remaining in the body for a shorter time than other inhaled halogenated anesthetics (Eger et al., 2002). This trait is beneficial for obese patients and long-term operation. In fact, after 2 h of isoflurane exposure, 99.9% brain elimination time was about 2 days, whereas desflurane requires only about 1.5 days for more than 6 h of exposure (Lockwood, 2010). To investigate the long-term postanesthetic effects of desflurane comparing to isoflurane, we determined that 6-h exposure to 8.0% desflurane was appropriate.

Arterial blood gases were measured during anesthesia. Some of the mice in the desflurane group were decapitated after 6 h, and spurted blood, mainly arterial blood, was immediately collected (~200 μl) and analyzed using a Rapidlab 860 blood gas analyzer (Bayer HealthCare Diagnostics, Tarrytown, New York, USA).

Behavioral test batteries

Behavioral experiments started 1 week after anesthesia. The animals were handled for a short time each day after desflurane exposure. In order to comprehensively assess the effects of desflurane on the behavior of adult mice, we conducted seven well established and comprehensive behavioral test batteries (McIlwain et al., 2001; Paylor et al., 2006; Yonezaki et al., 2015), namely sensory, motor, anxiety, depression, sociability, attention, and learning test batteries, as outlined in Supplementary Fig. 1, Supplemental digital content 1, http://links.lww.com/BPHARM/A49, which minimize potential carry-over effects between behavioral tests. Each behavioral test battery started when the mice were 8 weeks old (control group, n = 10–11 per test battery; desflurane-treated group, n = 10 per test battery) and ended at 9 weeks of age. At the beginning of each test battery, each mouse was observed to check their general health (Supplementary Table 1, Supplemental digital content 2, http://links.lww.com/BPHARM/A50), and subjected to neurological screening tests (Miyakawa et al., 2001; Crawley, 2007; Takase et al., 2012). The whole behavioral methodology was essentially equivalent to that used in our previous investigation (Yonezaki et al., 2015), with minor modifications; the detailed methodology of each test is described in the Supplementary Text, Supplemental digital content 2, http://links.lww.com/BPHARM/A50.

Sensory test battery

To evaluate sensory function, neurophysiological measures were assessed using the following six tests: (1) visual function was assessed by the visual placing test (Heyser, 2003; Crawley, 2007; Takase et al., 2012). This test involves holding the mouse by its tail approximately 30 cm above a flat table surface. As the mouse is gradually lowered to the table, it extends its forepaws for a ‘soft landing’. (2) Auditory function was assessed by the Preyer reflex test (Henry and Willott, 1972; Huang et al., 1995; Crawley, 2007; Takase et al., 2012). The Preyer reflex is a flinch response to the sound of a loud hand clap. (3) Tactile function was assessed using the Von Frey hair touch test (Fuchs et al., 1999; Pitcher et al., 1999; Crawley, 2007). The mouse stood on an elevated platform with wide gauge wire mesh on the surface. The Von Frey hair (2.9 N) was inserted through the holes in the mesh from below to poke the undersurface of a hind paw. If the mouse quickly flicked its paw away from the Von Frey hair in two out of three consecutive trials, its tactile ability was recorded as normal. (4) Gustatory function was assessed using the two-bottle choice test (Crawley, 2007; Takase et al., 2012). During a 24-h habituation period, the mouse was allowed to drink from two bottles containing water. After the habituation period, one of the two bottles was replaced with a bottle containing 5% sucrose, and consumption monitored for 24 h. The preference for sucrose was calculated using the following formula: Preference (%) = sucrose consumption (g)/total consumption (g) × 100. (5) Olfaction was assessed by an olfactory habituation/dishabituation test (Wrenn et al., 2003; Silverman et al., 2010). The odorant stimuli were tap water, vanilla extract, and bitter almond extract. A stimulus-soaked cotton swab was presented for 3 minutes and then replaced with a fresh swab scented with the same odorant for a total of three presentations of each stimulus, and nine total olfactory stimulus presentations. An experimenter recorded the cumulative time that the mice spent sniffing the cotton swab. (6) Thermal pain sensitivity was assessed by a hot-plate test (Blakeman et al., 2003; Crawley, 2007). The hot-plate test was performed by placing the mouse on a metal surface (Muromachi Kikai, Tokyo, Japan) maintained at 54 ± 0.1°C. The latency to jumping off the plate or licking a hind paw was recorded.

Motor test battery

To evaluate motor function, motor coordination, balance, and grip strength were assessed by the following three tests: (1) motor coordination and balance were assessed by the rotarod test (Holmes et al., 2001; Paylor et al., 2006) using an accelerating rotarod (Muromachi Kikai). Mice were placed on a cylinder that slowly accelerated from 4 to 40 rpm for a maximum of 300 seconds, and the latency to fall was recorded. Each mouse performed three trials. (2) Motor coordination and balance were also assessed by the balance beam test (Carter et al., 1999). The mice were allowed up to 60 seconds to traverse a narrow beam. The beams were square or round strips of metal 1 m long with a cross-section of 5, 12, or 28 mm or a diameter of 11, 17, or 28 mm. The beams were placed horizontally 50 cm above the floor, with one end attached to an enclosed box into which the mice could escape. During training (1 day), mice were placed at the start of the 12-mm square beam and trained for six trials to traverse the beam to the enclosed box. Twenty-four hours after training, each mouse performed one trial on each of the square beams and each of the round beams, progressing from the narrowest to the widest. The latency to traverse each beam and the number of times the hind feet slipped off were recorded for each trial. (3) Balance and grip strength were assessed using the wire hang test (Crawley, 2007; Sango et al., 1996; Takase et al., 2012). The test was performed by placing the mouse on the top of a wire cage lid. The upside-down lid was held approximately 40 cm above the cage litter. Each mouse performed two trials. The investigator used a stopwatch to time the latency in falling off the wire lid, with a maximum of 60 seconds.

Anxiety test battery

To evaluate the anxiety-like behavior of mice, spontaneous and innate behavioral responses were measured by the following three tests: (1) anxiety-like response to unprotected open environment was assessed by an elevated plus maze test (Holmes et al., 2002a,2002b; Holmes et al., 2003). The mice were allowed to explore for 5 minutes the apparatus consisting of two open arms and two closed arms extending from a central platform and elevated 40 cm above the floor. The time spent in the open arms and the number of entries in the open and the closed arm were scored by a behavioral scoring software (ANY-maze; Stoelting, Wood Dale, Illinois, USA). (2) Anxiety-like response to a novel open environment was assessed using an open field test (Paylor et al., 1998). The mouse was allowed to explore a gray polypropylene chamber (50 × 50 × 40 cm) in 70 lx lighting conditions. Activity in the open field was automatically quantified using TimeOFCR4 (O’Hara, Tokyo, Japan). Activity in the center (30 × 30 cm), total distance and time spent in the center were recorded for 10 minutes. (3) Anxiety-like response to a lit environment was assessed by using a light-dark exploration test (Mathis et al., 1994; Holmes et al., 2002a,2002b; Holmes et al., 2003). The mice were allowed to explore for 10 minutes the apparatus, which consisted of an open-topped ‘light’ compartment (1000 lx) and a close-topped ‘dark’ compartment, separated by a partition with a small aperture (Muromachi Kikai). The number of transitions between the two compartments and the total time spent in the dark compartment were recorded by the ANY-maze.

Depression test battery

To evaluate the depression-like state, the behavioral immobility trait known as ‘learned helplessness’ was assessed by the following two tests: (1) antidepressant activity was assessed by the Porsolt forced swim test (Porsolt et al., 1977; Borsini and Meli, 1988). Each mouse was placed in a Plexiglas cylinder filled with water and allowed to swim for 6 minutes. The duration of immobility during the last 4 minutes was measured using ANY-maze. (2) Antidepressant activity was also assessed by the tail suspension test (Holmes et al., 2002a,2002b; Cryan and Mombereau, 2004). Each mouse was suspended by the tail 30 cm above the ground for 6 minutes using medical adhesive tape. The latency to first immobility and the time of immobility were measured with ANY-maze.

Sociability test battery

To evaluate sociability, social exploratory behavior and social dominance were assessed by the following two tests: (1) social behavior was examined using a social interaction test (Crawley, 2007; Silverman et al., 2010; Yonezaki et al., 2015). Each mouse was allowed to explore an unfamiliar male mouse in a chamber (30 × 36 × 17 cm) for 5 minutes. The interaction frequency and total duration of the interaction were recorded. (2) Social dominance was examined using a tube test (Lindzey et al., 1961). Two mice were released simultaneously at opposite ends of a transparent tube 30 cm long with an inside diameter of 3 cm. The first mouse to retreat from the tube within 2 minutes was designated as the ‘loser’. The winning percentage of each group was calculated as the number of wins over total trials. Paired encounters between mice in the control and desflurane-treated groups were arranged based on body weight.

Attention test battery

To evaluate attentional function, sensory-motor gating and learned selective attention were assessed by the following two tests: (1) sensory-motor gating was assessed by a prepulse inhibition test (Miyakawa et al., 2003) using a startle reflex measurement system (O’Hara). After 5-minute acclimation to background noise (70 dB), the test session consisting of six blocks was presented. A block consisted of two pulse-only trials (40 ms, 110 and 120 dB) and four combinations of prepulse-pulse trials (74–110, 78–110, 74–120, and 78–120 dB), which were presented in pseudorandom order. The average inter-trial interval was 15 seconds (range 10–20 seconds). The percentage of prepulse inhibition was calculated as follows: [(startle response for pulse alone − startle response for pulse with prepulse)/startle response for pulse alone] × 100. (2) Learned selective attention was assessed by using a latent inhibition test (Miyakawa et al., 2003). On the first day, each mouse was placed in a conditioning chamber (Muromachi Kikai). The mice were divided into two groups: pre-exposed (P) and non-pre-exposed (NP). The P group was exposed to 40 samples of white noise (68 dB, duration 5 seconds, inter-stimulus interval 25 seconds), and the NP group was exposed to no stimulus during an equivalent period. Immediately after the pre-exposure period, all mice were given a combination of white noise and foot shock (2 seconds, 0.4 mA) twice with a 25-second inter-stimulus interval. On day 2, the mice were placed in the conditioning chamber for 5 minutes to measure context freezing. On day 3, the mice were put in a white Plexiglas chamber scented with vanilla essence, and after 180 seconds, a 180-second sample of white noise was delivered to measure cued freezing.

Learning test battery

To evaluate learning ability, recognition memory and associative memory were assessed by the following three tests: (1) recognition memory about place and object was assessed by a novel place/object recognition test (Ng et al., 2009). The test consisted of three sessions with intersession intervals of 2 minutes. Each mouse was initially allowed to explore four different objects for 15 minutes in a chamber (30 × 36 × 17 cm). Second, for the place recognition session, two of the four objects were moved to the opposite side of the chamber. Third, for the object recognition session, one of the two familiar objects was replaced with a novel object. The time spent exploring the objects was recorded for 5 minutes. The percentage of time spent exploring the displaced or novel object over the total exploring time was calculated. (2) Recognition memory about other individuals was assessed by a social recognition test (Crawley, 2007; Silverman et al., 2010; Yonezaki et al., 2015). In the sample phase, mice were placed in a chamber with a naive mouse for 10 minutes. One hour later, in the test phase, the mouse was returned to the chamber and exposed to the same mouse and a novel mouse for 10 minutes. Novelty preference was assessed by the percentage of interaction time with the novel mouse over the total interaction time. (3) Associative memory was assessed by the contextual/cued fear conditioning test (Miyakawa et al., 2003). The procedure was identical to the procedure used in the NP group in the latent inhibition test described above.

Additional test battery

Due to the limited time, space and life resources, the sample size in this study might be too small to get a sufficient conclusion. In addition, desflurane may affect behavior in more early time point. To address these issues, first, we calculated the effect size of each evaluation item based on the results of present study as a measure of effects independent of sample size. Second, we built up a new additional test battery consisting of behavioral tests that showed enough large effect size (according to Cohen’s criterion). Finally, this additional test battery carried out 1 day or 3 days after exposure to desflurane. Considering the result of comprehensive behavioral test batteries, the additional test battery consisted of three tests, elevated plus maze, balance beam test and tale suspension test. We performed these tests in the order of elevated plus maze, balance beam test and tail suspension test with a 48 h interval. The detailed methodology of each test is according to the method described above.

Statistical analysis

In most cases, one-way analysis of variance (ANOVA) was performed with anesthesia (control- or desflurane-treated) as the independent variable. For the olfactory habituation/dishabituation test, rotarod test, balance-beam test, hanging wire test, prepulse inhibition test, latent inhibition test, and contextual/cued fear conditioning test, two-way or three-way ANOVA with repeated measures was performed using anesthesia and another variable (odor, trial, beam, startle stimulus, or time) as independent variables. These tests were followed by post-hoc analysis with Shaffer’s modified sequentially rejective Bonferroni procedure. Chi-squared tests were used to evaluate differences between the two groups in the general health check, neurological screening test, visual placing test, Preyer reflex test, Von Frey hair touch test, and tube test, because the assessed variables were categorical (i.e. ‘normal’ or ‘abnormal’, and ‘win’ or ‘lose’ were recorded). Differences were considered significant for P < 0.05. The data in each group for the contextual/cued fear conditioning test were reanalyzed as the data for the NP group in the latent inhibition test. All statistical analyses were performed using the SPSS software, version 20.0 (IBM, New York, USA).

Results

General condition of the mice

Arterial blood gas results were similar between the two groups (pH, NS; pCO2, NS, Table 1). The general health check and neurological screening indicated good general health and normal gross appearance for all mice (data not shown).

Table 1 - Effect of desflurane on arterial gases of mice
Group pH pCO2
Control 7.37 (0.01) 35.87 (1.30)
Desflurane 7.34 (0.02) 38.13 (1.85)
No significant differences were observed between the groups. Values are mean (SEM).

Sensory functions

All mice in the control and desflurane-treated groups displayed similar responses during the visual placing test, Preyer reflex, and Von Frey hair touch test (data not shown). Further, both groups showed similar preferences for sucrose (F (1, 18) < 0.01, NS, η2 < 0.001, Fig. 1a). In the olfactory habituation/dishabituation test, both groups showed similar levels of sniffing of a cotton swab dipped in water, vanilla, and bitter almond (main effect of anesthesia: F (1, 36) = 0.05, NS, partial η2 = 0.003; main effect of odor: F (2, 36) = 3.18, P < 0.1, partial η2 = 0.150; main effect of trial: F (2, 36) = 66.96, P < 0.001, partial η2 = 0.788; all of interactions between these factors were NS; Fig. 1b). The mean latency for jumping off the plate or licking a hind paw in the hot-plate test were similar in both groups (F (1, 18) = 0.31, NS, η2 = 0.017, Fig. 1c).

Fig. 1
Fig. 1:
Effect of desflurane exposure on sensory functions of mice. These data showed that desflurane had no postanesthetic effects on sensory functions. (a) Effect of desflurane exposure on gustatory function assessed by the two bottle choice test. The mean percentage sucrose solution consumption of the total liquid consumption of each group is shown. Sucrose preference = sucrose consumption (g)/total consumption (g) × 100, where 50% indicates no differences in both liquid consumption. (b) Effect of desflurane exposure on olfactory function assessed by the olfactory habituation/dishabituation test. The mean sniffing time to a cotton swab dipped in water, vanilla, and bitter almond of each group is shown. (c) Effect of desflurane exposure on thermal pain sensitivity assessed by the hot-plate test. The mean latency for jumping off the plate or licking a hind paw of each group is shown.

Motor functions

In the rotarod test, the mean latency for falling off the rod increased through the trials in both the control and the desflurane-treated groups (main effect of anesthesia: F (1, 17) = 0.14, NS, partial η2 = 0.008; main effect of trial: F (2, 34) = 2.91, P < 0.1, partial η2 = 0.146; interaction: F (2, 34) = 0.14, NS, partial η2 = 0.081; Fig. 2a), suggesting normal motor learning function. Furthermore, this test indicated similar motor coordination in the two groups. In the balance-beam test, the mean latency to traverse (main effect of anesthesia: F (1, 17) = 3.71, P < 0.1, partial η2 = 0.179; main effect of trial: F (5, 85) = 174.05, P < 0.001, partial η2 = 0.911; interaction: F (5, 85) = 0.30, NS, partial η2 = 0.017; Fig. 2b) and the mean number of times the hind feet slipped off in the training phase decreased through the trials in both groups (main effect of anesthesia: F (1, 17) = 1.38, NS, partial η2 = 0.075; main effect of trial: F (5, 85) = 72.50, P < 0.001, partial η2 = 0.810; interaction: F (5, 85) = 1.67, NS, partial η2 = 0.090; Fig. 2c), suggesting normal motor learning function. Further, these results indicated similar motor coordination in the two groups. In the test phase of balance-beam test, the mean latency to traverse (main effect of anesthesia: F (1, 17) = 2.23, NS, partial η2 = 0.116; main effect of beam: F (5, 85) = 17.82, P < 0.001, partial η2 = 0.512; interaction: F (5, 85) = 0.31, NS, partial η2 = 0.018; Fig. 2d) and the mean number of times the hind feet slipped off in each beam (main effect of anesthesia: F (1, 17) = 2.90, NS, partial η2 = 0.146; main effect of beam: F (5, 85) = 57.53, P < 0.001, partial η2 = 0.772; interaction: F (5, 85) = 1.31, NS, partial η2 = 0.071; Fig. 2e) also suggest similar motor coordination. The mean latency for falling off in the hanging wire test indicated similar balance and grip strength in the two groups (F (1, 17) = 0.90, NS, η2 = 0.050; Fig. 2f).

Fig. 2
Fig. 2:
Effect of desflurane exposure on motor functions of mice. These data showed that desflurane had no postanesthetic effects on motor functions. (a) Effect of desflurane exposure on motor coordination and balance assessed by the accelerating rotarod test. The mean latency for falling off the rod increased through the trials of each group is shown. (b–e) Effect of desflurane exposure on motor coordination and balance assessed by measuring the ability of the mice to traverse a graded series of narrow beams to reach an enclosed safety platform (balance-beam test). (b) The mean latency to traverse the beam in the training phase of balance-beam test of each group is shown. (c) The mean number of times the hind feet slipped off in the training phase of the balance-beam test of each group is shown. (d) The mean latency to traverse in each beam (i.e. square small, square medium, square large, round small, round medium, or round large bar) in test phase of balance-beam test of each group is shown. (e) The mean number of times the hind feet slipped off in each beam of each group is shown. (f) Effect of desflurane exposure on balance and grip strength assessed by the wire hang test. The mean latency to falling off the wire of each group is shown. Data are shown as mean ± SEM. L, large; M, medium; S, small.

Anxiety

In the elevated plus maze, the mean time spent in the open arm was longer in the desflurane treated mice than in the control group, but the difference did not reach statistical significance (F (1, 18) = 2.61, NS, η2 = 0.127; Fig. 3a). No significant differences were observed between the two groups in the rate of open entries in the elevated plus-maze (F (1, 18) = 0.52, NS, η2 = 0.028; Fig. 3b), the mean percentage time in open arms (F (1, 18) = 2.38, NS, η2 = 0.117; Fig. 3c), the mean time spent in the central area in the open field test (F (1, 18) = 0.01, NS, η2 < 0.001; Fig. 3d), the distance ratio of center area in the open field test (F (1, 18) = 0.03, NS, η2 = 0.002; Fig. 3e) and the time spent in the dark compartment during the light-dark exploration test (F (1, 18) = 1.01, NS, η2 = 0.053; Fig. 3f).

Fig. 3
Fig. 3:
Effect of desflurane exposure on anxiety-like behaviors of mice. Desflurane-treated mice exhibited no postanesthetic effects in any behavioral tests. (a–c) Effect of desflurane exposure on innate anxiety-like behavior assessed by elevated plus maze. (a) The mean time spent in the open arms of the elevated plus maze of each group is shown. (b) The mean percentage of open arms entries of the elevated plus maze of each group is shown. (c) The mean percentage of time spent in open arms of the elevated plus maze of each group is shown. (d and e) Effect of desflurane exposure on innate anxiety-like behavior also assessed by open field test. (d) The mean time spent in the center area of the open field of each group is shown. (e) The mean percentage of distance traveled in center area out of total distance in the open field of each group is shown. (f) Effect of desflurane exposure on innate anxiety-like behavior also assessed by the light-dark exploration test. The mean time spent in dark compartment of light-dark exploration test of each group is shown. Data are shown as mean ± SEM. P > 0.050.

All mice in the conThe time of immobility during the Porsolt forced swim test was similar in the two groups (F (1, 18) = 0.18, NS, η2 = 0.010; Fig. 4a). The tail suspension test also showed no significant differences between the groups (F (1, 18) = 2.61, NS, η2 = 0.127; Fig. 4b).

Fig. 4
Fig. 4:
Effect of desflurane exposure on depression-like behaviors of mice. Desflurane-treated mice exhibited no postanesthetic effects in any behavioral tests. (a) Effect of desflurane exposure on depression-like behavior assessed by the Porsolt forced swim test. The mean immobile time during last 4 minutes of each group is shown. (b) Effect of desflurane exposure on depression-like behavior also assessed by the tail suspension test. The mean latency to first immobile episode of each group is shown. Data are shown as mean ± SEM. P > 0.050.

Sociability

In the social interaction test, the interaction times per contact were similar in the two groups (F (1, 18) = 0.62, NS, η2 = 0.004; Fig. 5a), and so were the winning percentages in the tube test (χ2 = 0.8, NS, Ø = 0.20; Fig. 5b).

Fig. 5
Fig. 5:
Effect of desflurane exposure on sociality of mice. Desflurane-treated mice exhibited no postanesthetic effects in any behavioral tests. (a) Effect of desflurane exposure on sociality assessed by the social interaction test. The mean interaction time per contact of each group is shown. (b) Effect of desflurane exposure on social dominance/aggressiveness assessed by the tube test. The winning percentage of each group is shown. Data are shown as mean ± SEM, except winning percentages in the tube test.

Attention

In the prepulse inhibition test, the control and desflurane-treated groups showed similar levels of startle response to each startle stimuli: in both groups, the more intense the pulse, the larger the response (main effect of anesthesia: F (1, 18) = 1.32, NS, partial η2 = 0.068; main effect of pulse: F (1, 18) = 40.10, P < 0.001, partial η2 = 0.690; interaction: F (1, 18) = 0.71, NS, partial η2 = 0.038; Fig. 6a). The percentage of prepulse inhibition was also similar in the two groups. A three-way ANOVA (anesthesia × prepulse × pulse) revealed that there were no significant differences (main effect of anesthesia: F (1, 18) = 0.11, NS, partial η2 = 0.006; main effect of prepulse: F (1, 18) = 2.96, NS, partial η2 = 0.141; main effect of pulse: F (1, 18) = 2.53, NS, partial η2 = 0.123; all of interactions between these factors were NS; Fig. 6b). In the latent inhibition test, both control and desflurane-treated groups displayed latent inhibition effect; the P group had significantly lower freezing levels during the white noise presentation period than did the NP group. A three-way ANOVA [anesthesia × pre-exposure × conditioned stimulus (CS)] revealed that significant main effects of Pre-exposure F (1, 36) = 12.11, P < 0.001, partial η2 = 0.252) and CS (F (1, 36) = 452.72, P < 0.001, partial η2 = 0.926, and significant interaction between these factors F (1, 36) = 7.84, P < 0.01, partial η2 = 0.179, whereas main effect of Anesthesia F (1, 36) < 0.01, NS, partial η2 < 0.001 and interactions between Anesthesia and other factors were NS (Ps > 0.1). A post-hoc test revealed a significant difference between NP group and P group only while white noise was presented (pre-CS: F (1, 36) = 3.08, P < 0.1, partial η2 = 0.079, Fig. 6c; during-CS: F (1, 36) = 11.92, P < 0.001, partial η2 = 0.249, Fig. 6d).

Fig. 6
Fig. 6:
Effect of desflurane exposure on attention of mice. Desflurane-treated mice exhibited no postanesthetic effects in any behavioral tests. (a and b) Effect of desflurane exposure on sensory-motor gating, an involuntary information filtering system, assessed by prepulse inhibition test. (a) The mean magnitude of acoustic startle response evoked by 110 and 120 dB white noise of each group is shown. Both desflurane-treated and control groups showed increment in startle responses with increasing stimulus intensity. (b) The mean percentage of prepulse inhibition to each pulse (110 and 120 dB) preceded by each prepulse (74 and 78 dB) of each group is shown. The percentage of prepulse inhibition was calculated as follows: [(startle response for pulse alone − startle response for pulse with prepulse)/startle response for pulse alone] × 100. Both desflurane-treated and control groups showed same level of prepulse inhibition. (c and d) Effect of desflurane exposure on learned selective attention, the ability to learn to ignore irrelevant information, assessed by latent inhibition test. Weaker conditioned response (i.e. lower percentage of freezing) in the pre-exposed groups (P) compared to the non-pre-exposed groups (NP) during conditioned stimulus (CS; i.e. white noise) presentation reflects the latent inhibition effect. (c) The mean percentage of freezing in pre-CS presentation of each NP and P group is shown. There were no differences in percentage of freezing between NP and P groups, and between desflurane-treated and control groups. (d) The mean percentage of freezing during CS presentation of each NP and P group is shown. Both desflurane-treated and control groups showed similar latent inhibition effect (i.e. lower percentage of freezing in P groups than NP groups). Data are shown as mean ± SEM. *P < 0.001. NP, non-pre-exposed; P, pre-exposed.

Learning functions

In the novel place/object recognition test, control and desflurane-treated groups showed similar exploring times during the habituation period. Furthermore, both groups showed similar tendency to explore displaced and novel objects (Place: F (1, 18) = 0.09, NS, η2 = 0.005; objects: F (1, 18) = 0.07, NS, η2 = 0.004; Fig. 7a). In the social recognition test, the two groups showed similar tendency to explore the novel mouse (F (1, 18) = 1.05, NS, η2 = 0.055; Fig. 7a). In the contextual fear conditioning test, the two groups displayed a similar level of freezing during the contextual. A two-way ANOVA (anesthesia × time) revealed that both groups followed similar time courses (main effect of anesthesia: F (1, 18) = 0.30, NS, η2 = 0.016; main effect of time: F (4, 72) = 4.84, P < 0.005, partial η2 = 0.212; interaction: F (4, 72) = 0.94, NS, partial η2 = 0.050; Fig. 7b). In the cued fear conditioning test, the same tendency as contextual fear conditioning was observed. A three-way ANOVA (anesthesia × CS × time) revealed that both groups showed CS induced increment in freezing with similar time courses (main effect of anesthesia: F (1, 18) = 0.02, NS, η2 = 0.001; main effect of CS: F (1, 36) = 410.24, P < 0.001, partial η2 = 0.958; main effect of time: F (2, 36) = 12.97, P < 0.001, partial η2 = 0.419; all of interactions between these factors were NS; Fig. 7c).

Fig. 7
Fig. 7:
Effect of desflurane exposure on learning and memory of mice. Desflurane-treated mice exhibited no postanesthetic effects in any behavioral tests. (a) Effect of desflurane exposure on recognition memory about place, object and other individual assessed by novel place/object recognition test and social recognition test. The mean percentage of novelty exploring time in the novel place recognition test (Place), novel object recognition test (Object) and social recognition test (Mouse) is shown. (b and c) Effect of desflurane exposure on the hippocampus-dependent/non-dependent associative learning ability assessed by contextual/cued fear conditioning test. (b) The mean percentage of freezing during contextual test of each group is shown. (c) The mean percentage of freezing pre- and during CS presentation of each group in cued fear conditioning test is shown. Data are shown as mean ± SEM.

Additional test battery

To assess the time course of postanesthetic effect on candidates of behavioral tests that likely to be affected by desflurane, we built up a new additional test battery. We selected three behavioral tests that factor of anesthesia showed medium-large to large effect size (η2 > 0.109) in the results of present study: balance-beam test (latency to traverse in the training; partial η2 = 0.179), elevated plus maze (time spent in the open arm; η2 = 0.127), and tail suspension test (latency to first immobile episode; η2 = 0.127). This additional test battery carried out 1 day or 3 days after exposure to desflurane. In the elevated plus maze, no significant differences were observed between the three groups in the mean time spent in the open arm (F (2, 29) = 0.08, NS, η2 = 0.005; Fig. 8a) and the rate of open arm entries (F (1, 29) = 0.36, NS, η2 = 0.024; Fig. 8b). In the training phase of balance-beam test, the mean latency to traverse decreased through the trials in all three groups [main effect of trial; F (5, 145) = 44.66, P < 0.001, η2 = 0.606; main effect of anesthesia and these interaction was NS (Ps > 0.1); Fig. 8c); Fig. 8c], suggesting normal motor learning function. On the other hand, the mean number of slips exhibit significant interaction with Anesthesia and Trial (F (10, 145) = 4.64, P < 0.001, partial η2 = 0.242; Fig. 8d), as well as main effect of trial (F (5, 145) = 25.46, P < 0.001, partial η2 = 0.468; Fig. 8d). A post-hoc analysis revealed that mice treated with desflurane 1 day before testing showed more slips than other two groups in the first trial. In the testing phase of balance-beam test, the mean latency to traverse in the narrowest square beam was longer than other beams in all three groups (main effect of beam; F (5, 145) = 5.56, P < 0.001, partial η2 = 0.161; main effect of anesthesia and these interaction was NS (Ps > 0.1), Fig. 8e). Similarly, mean number of slips in the narrowest square beam was more than other beams, and narrowest round beam was more than other round beams (main effect of beam; F (5, 145) = 14.09, P < 0.001, partial η2 = 0.327; main effect of group and these interaction was NS (Ps > 0.1), Fig. 8f). In the tail suspension test, no significant differences were observed between the three groups in the mean latency to first immobile episode (F (2, 29) = 0.19, NS, η2 = 0.013; Fig. 4g).

Fig. 8
Fig. 8:
Time course of postanesthetic effect of desflurane on additional test battery of mice. Any desflurane-treated mice exhibited no postanesthetic effects in almost all behavioral tests, except number of times the hind feet slipped off in the first trial of training phase of balance beam test (d). (a and b) Effect of desflurane exposure on innate anxiety-like behavior assessed by elevated plus maze. (a) The mean time spent in the open arms of the elevated plus maze of each group is shown. (b) The mean percentage of open arms entries of the elevated plus maze of each group is shown. (c–f) Effect of desflurane exposure on motor coordination and balance assessed by measuring the ability of the mice to traverse a graded series of narrow beams to reach an enclosed safety platform (balance-beam test). (c) The mean latency to traverse the beam in the training phase of balance-beam test of each group is shown. (d) The mean number of times the hind feet slipped off in the training phase of the balance-beam test of each group is shown. (e) The mean latency to traverse in each beam (i.e. square small, square medium, square large, round small, round medium, or round large bar) in test phase of balance-beam test of each group is shown. (f) The mean number of times the hind feet slipped off in each beam of each group is shown. (g) Effect of desflurane exposure on depression-like behavior assessed by the tail suspension test. The mean immobile time of each group is shown. Data are shown as mean ± SEM. *P < 0.05.

Discussion

We performed systematic comprehensive behavioral test batteries in mice exposed to desflurane. Previous reports examined the postanesthetic effects of desflurane on a limited set of behavioral phenotypes (Kilicaslan et al., 2013; Tang et al., 2013; Callaway et al., 2015), but our study is the first to systematically investigate its effects on general health, fundamental behavior, and higher behavioral functions. The exposure to 8.0% desflurane for 6 h induced no postanesthetic effects in any behavioral test performed 7 days after anesthesia, suggesting that desflurane did not cause long-lasting changes in sensory functions, motor functions, anxiety, depression, sociability, attention, or learning abilities of the mice. Nevertheless, mice treated with desflurane 1 day before testing showed more slips than other two groups in the first trial. These results suggest mild acute side effects of desflurane on motor coordination. Our behavioral test battery has previously revealed new aspects of anesthetics with high sensitivity, proving its usefulness in presenting comparable data for various kinds of anesthetics with the same method. We have so far focused on halogenated ethers, but the same system can also be easily applied to intravenous anesthetics.

We previously reported the postanesthetic effects of isoflurane in adult rats and mice. Isoflurane impairs hippocampus-dependent learning performance in rats (Uchimoto et al., 2014) in addition to leading to attention deficit during the latent inhibition test in mice (Yonezaki et al., 2015). Contrary to what was observed for isoflurane, desflurane-exposed mice exhibited normal performance in the latent inhibition test. These results demonstrate that these halogenated ethers, while sharing many sites of actions, also act on different specific sites. Our results lead to the hypothesis that overlapping sites of action (Rudolph and Antkowiak, 2004; Alkire et al., 2008; Franks, 2008) mainly contribute to the sedative, analgesic and muscle relaxant action, whereas specific sites of action may lead to specific postanesthetic behavioral effects.

A considerable number of behavioral tests have been constructed to mimic human behaviors for application to translational research (Takahashi et al., 1994; Bućan and Abel, 2002; Takao et al., 2008; Yamasaki et al., 2008; Matsuo et al., 2009; Nakatani et al., 2009). Our results suggest that desflurane may have no or less postanesthetic behavioral effects in humans up to 7 days after anesthesia. These findings may be in line with some previous human data showing that isoflurane, but not desflurane, impairs cognitive function measured by multiple tests 1 week after anesthesia (Zhang et al., 2012) and that the scores of trail-making tests performed 3 days after general anesthesia were better with desflurane than with sevoflurane (Rörtgen et al., 2010).

The present study does have limitation. The postanesthetic behavioral effects of desflurane may depend on the time course after anesthesia and anesthetic concentration. Since the latency to traverse in the balance-beam test, time spent in open arms in the elevated plus maze, and latency to immobility in the tail suspension test exhibited medium to large effect sizes (η2 = 0.179, 0.127, and 0.127, respectively), we built up a new additional test battery consisting of these behavioral tests. Further, this additional test battery carried out 1 day or 3 days after exposure to desflurane. As a result, we found that mice treated with desflurane 1 day before testing showed more slips than other two groups in the first trial, suggesting mild acute side effects of desflurane on motor coordination. In support of our results, we also found that desflurane impairs hippocampal learning in rats 1 day, but not 7 days, after anesthesia (Tojo et al., 2019).

In conclusion, desflurane did not cause long-lasting changes in sensory functions, motor functions, anxiety, depression, sociability, attention, or learning abilities of the mice. However, further studies are required to confirm the safety of desflurane in clinical settings, because the postanesthetic behavioral effects of desflurane may depend on anesthetic concentration. Nevertheless, this is the first report to systematically investigate the behavioral phenotypes of adult mice exposed to desflurane, and our present and previous findings (Yonezaki et al., 2015) suggest that the postanesthetic effects are unique to each halogenated ether.

Acknowledgements

We thank Ayako Asakura, MD, Department of Anesthesiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan, for insightful comments and advice on this article.

This work was supported by JSPS KAKENHI grant numbers 25293330 (https://kaken.nii.ac.jp/d/p/25293330.en.html) and 26670691 (https://kaken.nii.ac.jp/d/p/26670691.en.html) to T.G.

Conflicts of interest

There are no conflicts of interest.

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Keywords:

anesthesia; behavioral test battery; desflurane; halogenated ethers; rat

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