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Anesth Analg 2006;103:1459-1463
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000247792.03959.f1

ANESTHETIC PHARMACOLOGY

The Differential Effects of Nitrous Oxide and Xenon on Extracellular Dopamine Levels in the Rat Nucleus Accumbens: A Microdialysis Study

Sachiyo Sakamoto, MD*, Shinichi Nakao, MD, PhD*, Munehiro Masuzawa, MD, PhD*, Takefumi Inada, MD*, Mervyn Maze, MBChB, FRCP, FRCA, FMedSci{dagger}, Nicholas P. Franks, PhD, FMedSci{dagger}, and Koh Shingu, MD, PhD*

From the *Department of Anesthesiology, Kansai Medical University, Osaka, Japan and {dagger}Magill Department of Anaesthesia, Chelsea and Westminster Hospital and Biophysics Section, The Blackett Laboratory, Imperial College of Science, Technology and Medicine, London, United Kingdom.

Address correspondence and reprint requests to Shinichi Nakao, MD, Department of Anesthesiology, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi-shi, Osaka 570-8507, Japan. Address e-mail to nakaos{at}hirakata.kmu.ac.jp.


   Abstract
Top
 Abstract
Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Dopamine release in the nucleus accumbens (NAC) plays a crucial role in the action of various psychotropic and addictive drugs, such as antagonists of the N-methyl-d-aspartate subtype of the glutamate. Although both nitrous oxide and xenon are N-methyl-d-aspartate receptor antagonists, they differ in their potential for producing neuropsychological toxicity; therefore, we decided to examine their effects on both spontaneous and ketamine-induced extracellular dopamine levels in the NAC. A microdialysis probe was implanted into the NAC in each of 35 rats, which were randomly assigned to one of six groups: exposure to 40% O2, exposure to 60% nitrous oxide (0.27 MAC), exposure to 43% xenon (0.27 MAC) for 60 min, and three groups exposed to either 40% O2, 60% nitrous oxide, or 43% xenon for 70 min and 80 mg/kg ketamine was given i.p. 10 min after the initiation of gas exposure. Perfusate samples were collected every 20 min, and the dopamine levels were measured using a high-performance liquid chromatography system. Nitrous oxide, but not xenon, significantly increased the dopamine level. Ketamine significantly increased the dopamine level, and this was significantly inhibited by xenon, but not by nitrous oxide. These data suggest that the difference in neuropsychological activity between nitrous oxide and xenon is partly due to their differential effects on the mesolimbic dopamine system.


   Introduction
Top
 Abstract
 Introduction
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Most antagonists of the N-methyl-d-aspartate (NMDA) receptor subtype of the glutamate receptor exhibit psychotomimetic effects in humans, such as hallucination, agitation, and disorientation, and produce abnormal behavior in rodents (1,2). Paradoxically, although NMDA receptor antagonists have neuroprotective properties, these drugs also cause neuronal damage in the rat posterior cingulate and retrosplenial cortices (PC/RS). Olney et al. (1) proposed a hypothesis that the PC/RS are the brain loci responsible for the psychotomimetic effects and the etiology of schizophrenia. Although both xenon (3) and nitrous oxide (4) share a noncompetitive antagonistic action at the NMDA receptor, they differ in many other respects: Nitrous oxide can cause psychotomimetic effects (4) and be a drug of abuse (5), whereas there is no reported psychotomimetic or addictive potential for xenon. Nitrous oxide-induced neuronal damage in the rat PC/RS (4) is characterized by specific c-fos expression, a feature it shares with other NMDA receptor antagonists. It also enhances the injury produced by ketamine, another NMDA antagonist (6). In contrast, xenon does not induce c-fos expression itself (6,7) and even inhibits ketamine-induced c-fos expression (6).

The mesolimbic dopamine system (MLDS) consists of dopaminergic neurons in the ventral tegmental area (VTA) and the regions to which these neurons project, notably the nucleus accumbens (NAC). It plays a role in the etiology of psychosis and represents important neurobiological components for the rewarding effects of abusing drugs (8). Noncompetitive NMDA receptor antagonists, such as phencyclidine, MK-801, and ketamine, which are substances of abuse, cause abnormal behaviors in animals, such as hyperlocomotion and head weaving (9,10). The NMDA antagonist-induced behavioral state has been preferred as an animal model of schizophrenia (11) and is associated with the activation of dopaminergic neurons in the VTA and dopamine release in the NAC (11,12). Blockade of the dopamine receptor (probably the D2 receptor) with haloperidol prevents this behavioral state (13) and the associated neuronal injury in the PC/RS (7). We (12) previously demonstrated that ketamine significantly increased the extracellular dopamine levels in the NAC, which was inhibited by pentobarbital. However, there are no data addressing the effects of nitrous oxide and xenon on dopamine release in the NAC. In the present study, we first investigated whether nitrous oxide and xenon increased the dopamine levels in the NAC, and then examined the effect on the ketamine-induced dopamine level increase in the NAC. Based on the contrasting effects of nitrous oxide and xenon on the PC/RS, we hypothesized that nitrous oxide, but not xenon, would increase the dopamine level in the NAC, and that nitrous oxide would enhance the ketamine-induced dopamine level increase in the NAC, but that xenon would inhibit it.


   METHODS
Top
 Abstract
 Introduction
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals
The study was approved by the Animal Research Committee at Kansai Medical University. Thirty-five male Wistar rats weighing 250–300 g were randomly assigned to six groups. They were kept under controlled environmental conditions (ambient temperature 23°C–25°C, 12/12-h light–dark cycle, light on at 7:00 am) for at least 1 wk before being used. Food and tap water were allowed ad libitum. All experiments were performed between 10:00 and 16:00 h in a laboratory at an ambient temperature of 23°C–25°C.

Preparation
The rats were placed within a stereotaxic frame under pentobarbital anesthesia (50 mg/kg i.p.). A stainless steel guide cannula was stereotaxically implanted unilaterally into the NAC with the following coordinates in relation to the bregma, AP: +1.6, ML: +1.2, DV: –6.2 mm, according to the atlas by Paxinos and Watson (14). The cannula was fixed to the skull with dental resin and stainless steel screws. The location of the probe within the NAC was verified by visual examination at the end of each experiment. The animals were allowed to recover for at least 2 days. On the day of study, the stylet was removed from the cannula and a microdialysis probe (A-I-12-2, Eicom, Kyoto, Japan) was inserted through the cannula. After placing the rat in a plexiglass box (25 x 25 x 25 cm) in which it could move freely, the microdialysis probe was connected to the perfusion pump and to the sample loop of an automated sample injector (Model 10; Eicom, Kyoto, Japan) with polyethylene tubing. The microdialysis probe was perfused continuously with an artificial cerebrospinal fluid solution (NaCl 147 mM, KCl 4 mM, CaCl2 2.3 mM) at a rate of 2.0 µL/min.

Experimental Protocol
Perfusate samples obtained during the first 120 min after implantation of the probe were discarded. The dialysate samples were then collected every 20 min. After verifying the stability of baseline dopamine levels, three consecutive basal samples were collected. Just after obtaining the basal samples (sample 0), gas exposure was initiated.

Experiment 1 (Effects of Nitrous Oxide and Xenon on Dopamine Levels in the NAC)
In Group 1 (n = 5; control group), the rats were exposed to 60% N2 and 40% O2 for 60 min. In Group 2 (n = 6), the rats were exposed to 60% nitrous oxide (0.27 MAC) (15) and 40% O2 for 60 min. In Group 3 (n = 6), the rats were exposed to 43% xenon (0.27 MAC) (16), 40% O2, and 17% N2 for 60 min.

Experiment 2 (Effects of Nitrous Oxide and Xenon on Ketamine-Induced Dopamine Levels in the NAC)
In Group 4 (n = 7), the rats were exposed to 60% N2 and 40% O2 for 70 min and 80 mg/kg ketamine was given i.p. 10 min after the initiation of gas exposure. In Group 5 (n = 5), the rats were exposed to 60% nitrous oxide (0.27 MAC) and 40% O2 for 70 min and 80 mg/kg ketamine was given i.p. 10 min after the initiation of gas exposure. In Group 6 (n = 6), the rats were exposed to 43% xenon (0.27 MAC), 40% O2, and 17% N2 for 70 min and 80 mg/kg ketamine was given i.p. 10 min after the initiation of gas exposure.

The xenon concentration was continuously monitored using a xenon gas monitor (Anzai Sogyo, Tokyo, Japan). The nitrous oxide concentration was continuously monitored using an anesthetic gas monitor, Type 1304® (Brüel and Kjær, Nærum, Denmark).

Measurement of Dopamine Levels
Dopamine levels in the dialysates were measured using a high-performance liquid chromatography column equipped with an electrochemical detector. The samples were injected by an autoinjector into an ODS-C18 reverse-phase column (2.1 x 150 mm CA-5ODS: Eicom, Kyoto, Japan) maintained at 25°C. The mobile phase consisted of 0.1 M phosphate buffer (pH 6.0) containing 50 mg/L EDTA2Na, 500 mg/L 1-octanesulfonate, and 20% methanol and was run at a flow rate of 230 µL/min. The oxidation potential of the graphite electrode was set at 450 mV against an Ag/AgCl reference electrode (ECD-300, Eicom, Kyoto, Japan). The detection limit of the assay was 0.2 pg/ 40 µL.

Statistics
Changes in extracellular dopamine levels over time are expressed as a percentage of each group’s basal dopamine level (mean ± sd). After the dopamine level was considered to be stable, the basal level (sample 0) was taken as the mean of three initial collections (for 60 min) just before exposure to test drugs. Statistical evaluation was performed using the GraphPad Prism 4 (GraphPad Software, San Diego, CA). The differences within and among multiple groups over time were determined using two-way analysis of variance (ANOVA) with repeated measures, followed by Bonferroni’s test for multiple comparisons. P < 0.05 was considered statistically significant.


   RESULTS
Top
 Abstract
 Introduction
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Rats showed slight agitation during nitrous oxide exposure, but not during xenon exposure. Ketamine, at a dose of 80 mg/kg, induced abnormal behaviors, such as head weaving, sniffing, and ataxia. Nitrous oxide did not appear to affect the ketamine-induced behaviors, but xenon appeared to suppress them.

Figure 1 shows the effects of nitrous oxide and xenon on dopamine levels in the NAC. Nitrous oxide (0.27 MAC) induced a progressive elevation of dialysate dopamine levels, reaching a statistical significance after 40 min of nitrous oxide exposure; a maximum of 144% of the basal level was reached in the third perfusate sample (60–80 min epoch of nitrous oxide exposure). After the exposure to nitrous oxide was discontinued, the dopamine level gradually decreased to the basal level. The dopamine levels in the second and third perfusate samples of the nitrous oxide group were significantly higher than those in the control and xenon groups. In the fourth perfusate sample, the dopamine level in the nitrous oxide group was also significantly higher than in the xenon group. Conversely, xenon (0.27 MAC) did not affect the dopamine levels in the NAC, although a statistically insignificant decrease was seen.


Figure 126
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  		Figure 1. Effects of N2, xenon, and nitrous oxide on the dopamine level in the rat nucleus accumbens, as assayed by microdialysis in freely moving rats. The rats were continuously exposed to 40% O2, 43% xenon, or 60% nitrous oxide for 60 min. After verifying that dopamine levels were stable, the basal dopamine level was taken as the mean of three consecutive collections just before exposure to test gases. Data are expressed as mean (±sd) percent of basal values before drug injection. {blacktriangleup}: 40% O2 group; x: 43% xenon (0.27 MAC) group; {circ}: 60% N2O (0.27 MAC) group. *P < 0.05 versus basal values. #P < 0.05 versus O2 group at a given time. §P < 0.05 versus xenon group at a given time

 

Figure 2 shows the effect of nitrous oxide or xenon on ketamine-induced dopamine levels in the NAC. Ketamine, at a dose of 80 mg/kg i.p., induced a progressive elevation of dopamine levels in the NAC, reaching statistical significance in the second perfusate sample (40–60 min after ketamine i.p.). The dopamine levels remained elevated until the fourth sample (80–100 min), reaching a maximum of 243% of the basal level in the third sample. Nitrous oxide (0.27 MAC) did not affect the ketamine-induced dopamine levels in the NAC. On the other hand, the dopamine level in the third sample (60–80 min) of ketamine with 40% O2 was significantly higher than that of ketamine with xenon (0.27 MAC). Also, there was no significant increase in dopamine levels by ketamine with xenon.


Figure 226
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  		Figure 2. Effects of nitrogen, xenon, and nitrous oxide on the ketamine-induced dopamine level in the rat nucleus accumbens. The rats were given 80 mg/kg ketamine i.p. 10 min after the start of either 60% N2, 43% xenon, or 60% nitrous oxide exposure for 70 min. After verifying that dopamine levels were stable, the basal dopamine level was taken as the mean of three consecutive collections just before exposure to test gases. x: ketamine with 40% O2 exposure group; •: ketamine with 43% xenon (0.27 MAC) exposure group; {blacktriangleup}: Ketamine with 60% nitrous oxide (0.27 MAC) exposure group; *P < 0.05 versus basal values; #P < 0.05 versus ketamine with xenon group at a given time.

 


   DISCUSSION
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, we demonstrated that nitrous oxide, but not xenon, increased the dopamine level in the NAC, and that xenon significantly inhibited the ketamine-induced dopamine release in the NAC in freely moving rats.

Several potential limitations of our experiment should be considered. First, we did not systematically examine the behavioral changes in response to the test drugs because the main purpose of this experiment was to investigate dopamine release in the NAC. A correlation between dopamine release in the NAC and abnormal behavior induced by NMDA receptor antagonists such as MK-801 has been reported (11). Second, using the present experimental protocol, it was impossible to clarify whether the increase in dopamine levels in the NAC was due to an increase in dopamine release or a decrease in re-uptake. Because NMDA receptor antagonists activate VTA dopamine neurons (17), it is more probable that the dopamine level increase in the NAC induced by both ketamine and nitrous oxide can be attributed to an increase in dopamine release, rather than a decrease in dopamine re-uptake.

Nitrous oxide and xenon display a similar spectrum of receptor activity: both nitrous oxide and xenon potently inhibit not only NMDA receptors (3,4,18), but also nicotinic acetylcholine (nAch) receptors comprising the {alpha}4ß2 subunits, with no or little effect on {gamma}-aminobutyric acidA receptors and non-NMDA glutamate receptors (4,18). These gaseous anesthetics also exhibit similar clinical features; for example, both have analgesic action and cause similar electroencephalographic changes, exhibiting attenuation of {alpha} wave at lower concentrations, with the appearance of {theta}- and {delta}-wave activity at higher concentrations (19). A bispectral index value is not a reliable indicator for hypnosis in either xenon or nitrous anesthesia (20,21). However, their properties are quite different in various respects.

In the present study, we demonstrated that xenon can be differentiated from nitrous oxide with respect to its effects on the MLDS, suggesting that the contrasting neuropsychological properties of xenon and nitrous oxide can be, at least partially, attributed to their different effects on the MLDS. Both xenon and nitrous oxide are not only noncompetitive NMDA receptor antagonists, but also nAch receptor inhibitors (18). Although dopamine transmission in the MLDS is also regulated by cholinergic input (22), the effects of nitrous oxide and xenon on the MLDS do not seem to be mediated predominantly by their inhibitory effects on nAch receptors. This is because the dopamine release would have been inhibited if they acted predominantly at nAch receptors. Also, it is well established that NMDA receptor antagonists activate the MLDS and, consequently, induce psychotomimetic effects. Conversely, the inhibition of ketamine-induced dopamine release by xenon may be partly attributed to nAch receptor inhibition by xenon.

Xenon might not only have less psychotomimetic and addictive effects than nitrous oxide, but may also be protective against NMDA receptor antagonist-induced psychotomimetic effects and neurotoxicity, because dopamine is neurotoxic in some situations (23). Indeed, it has been demonstrated that xenon has neuroprotective effects in both in vivo and in vitro studies (24). Interestingly, the contrasting effects of nitrous oxide and xenon on the MLDS are consistent with their effects on the PC/RS, and independent studies have suggested that the MLDS and the PC/RS are the brain regions responsible for the psychotomimetic effects of NMDA receptor antagonists and the etiology of schizophrenia. Aalto et al. (25) recently demonstrated that ketamine increased dopamine release in the PC/RS not only in rats, but also in humans, although the role of the dopamine system in the PC/RS has not been clarified. Further studies will be required to elucidate the precise role of the dopamine system in the PC/RS and the relationship and/or neuronal networks between the PC/RS and the MLDS.

In conclusion, we demonstrated that nitrous oxide, but not xenon, increased the dopamine level in the NAC in freely moving rats, and that xenon inhibited the ketamine-induced increase in the dopamine level.


   Footnotes
 
Accepted for publication September 18, 2006.

Supported by Japan Society for the Promotion of Science Grant 16591572.

Nick Franks and Mervyn Maze are co-founders of an Imperial College London spin-out company, Protexeon; Protexeon had been issued with patents for the use of xenon as a neuroprotectant. Protexeon was acquired by Air Products. However, no funding was received from Air Products for this study.


   REFERENCES
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press