J Appl Physiol 107: 1951–1958, 2009.
First published August 20, 2009; doi:10.1152/japplphysiol.00097.2009.
TRANSLATIONAL PHYSIOLOGY
How can an inert gas counterbalance a NMDA-induced glutamate release?
Nicolas Vallee,1,2 Jean-Claude Rostain,2 and Jean-Jacques Risso1
1
Institut de Médecine Navale du Service de Santé des Armées, IRBA Toulon, Department of Marine and Underwater
Research, UMR-MD2, Toulon Cedex 9; and 2Université de la Méditerranée, Laboratoire de Physiologie et Physiopathologie
en Conditions d’Oxygénation Extrêmes, UMR-MD2, Institut Jean-Roche, Faculté de Médecine Nord, Marseille
Cedex 20, France
Submitted 30 January 2009; accepted in final form 19 August 2009
Vallee N, Rostain JC, Risso JJ. How can an inert gas counterbalance a
NMDA-induced glutamate release?. J Appl Physiol 107: 1951–1958, 2009.
First published August 20, 2009; doi:10.1152/japplphysiol.00097.2009.—
Previous neurochemical studies performed in rats have revealed a
decrease of striatal dopamine and glutamate induced by inert gas
narcosis. We sought to establish the hypothetical role of glutamate and
its main receptor, the N-methyl-D-aspartate (NMDA) receptor, in this
syndrome. We aimed to counteract the nitrogen narcosis-induced
glutamate and dopamine decreases by stimulating the NMDA receptor
in the striatum. We used bilateral retrodialysis on awake rats, submit-
ted to nitrogen under pressure (3 MPa). Continuous infusion of 2 mM
of NMDA under normobaric conditions (0.01 MPa) (n ⫽ 8) signifi-
cantly increased extracellular average levels of glutamate, aspartate,
glutamine, and asparagine by 241.8%, 292.5%, 108.3%, and 195.3%,
respectively. The same infusion conducted under nitrogen at 3 MPa
(n ⫽ 6) revealed significant lower levels of these amino acids (n ⫽
8/6, P ⬎ 0.001). In opposition, the NMDA-induced effects on dopa-
mine, dihydrophenylacetic acid (DOPAC), and homovanillic acid
(HVA) levels were statistically not affected by the nitrogen at 3 MPa
exposure (n ⫽ 8/6, P ⬎ 0.05). Dopamine was increased by ⬎240% on
average. HVA was decreased (down to 40%), and there was no
change in DOPAC levels, in both conditions. Results highlight that
the NMDA receptor is not directly affected by nitrogen under pressure
as indicated by the elevation in NMDA-induced dopamine release
under hyperbaric nitrogen. On the other hand, the NMDA-evoked
glutamate increase is counteracted by nitrogen narcosis. No improve-
ment in motor and locomotor disturbances was observed with high
striatal concentration in dopamine. Further experiments have to be
done to specify why the striatal glutamate pathways, in association
with the inhibition of its metabolism, only are affected by nitrogen
narcosis in this study.
dopamine; striatum; nitrogen narcosis; rat; anesthetic gas
DISRUPTION of motor and locomotor coordination, hallucina-
tions, sedation, and cognitive disturbances are symptoms of
nitrogen narcosis, which is visible in all mammals subjected to
increased nitrogen pressure. In humans, these symptoms occur
from 0.3 MPa [4 atmospheres absolute (ATA)], and a deep
nitrogen narcosis is obtained for 1 MPa (11 ATA). In rat, the
symptoms are visible from 1 MPa. A pressure of 4 MPa of
nitrogen is necessary to initiate anesthesia in rats (1), and a
deep nitrogen narcosis is obtained at 75% of the anesthetic
pressure threshold (3 MPa) (1, 7). Neurochemical studies have
Address for reprint requests and other correspondence: N. Vallee, Institut de
Médecine Navale du Service de Santé des Armées, IRBA Toulon, Dept. of
Marine and Underwater Research, UMR-MD2, BP 20548, 83049 Toulon
Cedex 9, France (e-mail: n.vallee@imnssa.net).
http://www. jap.org 8750-7587/09 $8.00 Copyright © 2009 the American Physiological Society
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focused on the rat striatum, where dopaminergic and N-methyl-
D-aspartate (NMDA) receptors are required for motor and
locomotor activity. Monitoring has thus revealed a decrease in
extracellular striatal concentrations of glutamate (43) and do-
pamine (DA) (3, 5, 17, 24, 38, 42), induced by inert gas
narcosis. It has been shown that decreased dopamine does not
result from the antagonistic effect of nitrogen on NMDA
receptors in the substantia nigra pars compacta (25, 26).
The striatal dopamine level is regulated by glutamate neu-
rotransmission and inversely (31, 32, 37). Corticostriate and
thalamostriate glutamatergic projections are the principal stri-
atal afferents (19, 41). They impinge on the projection of the
spiny neurons of the striatum, like dopamine inputs originating
from the substantia nigra pars compacta. The nigro-striatal
dopaminergic pathway is under direct glutamatergic control,
mediated by NMDA receptors located on dopaminergic neu-
rons (13, 34).
Considering previous studies, we hypothesized that stimu-
lating the NMDA receptor could increase both extracellular
striatal concentrations of glutamate and dopamine under nitro-
gen narcosis. It could also counteract motor and locomotor
disturbances, and the sedative effect induced by nitrogen nar-
cosis. We investigated the relationship between dopamine and
glutamate pathways under 3 MPa of nitrogen, using an NMDA
retrodialysis infusion. In the striatal extracellular space, gluta-
mate and its cotransmitter aspartate and their metabolites
glutamine and asparagine were be particularly targeted. Dopa-
mine and its metabolites, dihydrophenylacetic acid (DOPAC)
and homovanillic acid (HVA), were also analyzed. The neu-
rochemical study performed on metabolites indicated whether
nitrogen narcosis affects the neurotransmitter vesicular release
only.
MATERIALS AND METHODS
Animals
All procedures for the use of animals were in accordance with the
European Communities Council Rules (Brussels, Belgium) Directive
of November 24, 1986 (86/609/EEC), as stated in the French law
(decree 87/848), and experiments were conducted according to the
policies of our Institutional Animal Care and Use Committee (asso-
ciated with agreement number B13.0005.8). Male Sprague-Dawley
rats (Charles River) weighing 300 –350 g were used. Rats were kept
at 22 ⫾ 1°C under a 12:12-h light-dark cycle (lights on at 7:00 A.M.)
with food (A03, UAR) and water available ad libitum. After surgery,
rats were individually housed in Plexiglas cages where they recovered
for at least 1 wk before undergoing the microdialysis procedure. On
the day of the experiment, visual observation of the animal was
1951
1952 INERT GAS VERSUS GLUTAMATE RELEASE
conducted to reveal changes in behavioral signs, including the dis-
ruption of the motor and locomotor coordination and the sedative
effect induced by the nitrogen at 3 MPa, or some stereotyped activi-
ties.
Surgery
Anesthesia was induced by halothane (5% with O2) (Halothane,
Belamont) and then deeply prolonged with pentobarbital sodium (30
mg/kg ip) (Sanofi Santé Animal) and ketamine (0,40 mg/kg im;
Imalgène 500, Laboratoire Rhône-Mérieux). Rats were stereotaxically
implanted with two intracerebral guides (CMA/12 guide cannulae;
Phymep) in each striatum (from interaural: anterior 10.0 mm,
lateral 2.8 mm, height 6.4 mm) according to the atlas of Paxinos
and Watson (36).
Microdialysis in Hyperbaric Conditions
The microdialysis equipment consisted of microinjector pumps
(CMA/102; Phymep) customized to support high pressure, a
Raturn cage (Bioanalytical Systems,) to prevent fluid line tangling,
and two probes with a 3-mm-length membrane (CMA/12;
Phymep). HPLC switch valves, equipped with a loop of 20 ␮l,
were added to the microdialysis system, to propel the dialysate
toward the refrigerated microfraction collector (Univentor 820
Microsampler; Phymep) placed outside the hyperbaric chamber.
The various components of microdialysis devices were intercon-
nected by fluorinated ethylene propylene (FEP) tubing (1.2 ␮l/10
cm) or a polyetheretherketone (PEEK)-tubing (1.3 ␮l/10 cm), and
tubing adapters. The system was perfused by artificial cerebrospi-
nal fluid (CSF; in mmol/l: 147 NaCl, 2.7 KCl, 1.2 CaCl2, 0.85
MgCl2). This system was designed to collect regular samples to
freeze them as soon as possible, and not be limited by the number
of vials available in the collector, if the latter was placed inside the
hyperbaric chamber (43).
Concerning retrodialysis, two syringes perfused the rat brain, and
liquid switch connectors (CMA/110, Phymep) enabled manual switching
between the two perfusion lines, one of which contained the pharmaco-
logical agent (NMDA 3 ⫻ 10⫺3 M, Sigma).
The day before the experiment, new microdialysis probes were
rinsed for 20 min with 70% ethanol to wash out the glycerol used for
packaging. Each probe was then connected to the inlet microdialysis
line of the hyperbaric chamber and checked for air bubbles. Con-
nected to the outlet line, the entire dialysis line was then washed with
CSF overnight. Between experiments, the entire circuit was rinsed, for
at least 1 day, with methanol/water (40/60), and then air dried.
On the day of the experiment, at ⬃7:30 A.M., microdialysis probes
were inserted into the striatum of the awake rats. Extracellular levels
of amino acids and monoamines were allowed to be reconstituted
during 2 h and 40 min before the blank microdialysates (1 h 20 min
3 4 samples) were considered as basal value. Dialysates were
collected every 20 min at the rate of 1 ␮l/min (20 ␮l/dialysate) and
frozen.
Hyperbaric Procedure
Basal activities were monitored for 4 h before compression was
started. The experiments were conducted in a 150-liter hyperbaric
chamber fitted with two viewing portholes. Rats were compressed (40
min 3 2 samples) at a rate of 0.01 MPa/min up to 0.1 MPa and then
at a rate of 0.1 MPa/min up to 3 MPa. Monitoring was still running
during the stay under pressure (3 h 3 6 samples). Carbon dioxide
levels were kept below 300 ppm by continuous circulation of gases in
the chamber through a soda-lime canister. Oxygen partial pressure
was adjusted to 0.04 MPa (diving-quality oxygen, Air Liquide). A
powerful fan ensured that oxygen was well mixed with the gases
added, to generate narcosis. Humidity (40 – 60%) was controlled with
silicagel, and the ambient temperature was adjusted to 27°C (14) to
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prevent hypothermia and ensure that the rodents remained comfort-
able. Light was on. At the end of the experiment, a lethal dose of
nitrous oxide was injected into the hyperbaric chamber, and the
decompression was performed.
Concerning atmospheric experiments, rats were anesthetized with
halothane (5% with O2) (Halothane, Belamont) and killed by lethal
injection of pentobarbital.
Apparatus and Chromatography
Amino acid analyses. Microdialysis sample content was analyzed
by high-performance liquid chromatography (CMA/260 Degasser,
Kontron Instrument HPLC pump 422, HPLC pump 420, HPLC
Autosampler 465) coupled with fluorimetric detection (CMA/280
Fluorescence Detector). HPLC was carried out with a reverse-phase
C18 column (3 ␮m, 200 ⫻ 3 mm, Phymep) stabilized at 25°C under
gradient conditions. Eluent A consists of a sodium acetate buffer (0.01
M sodium acetate, 15% MeOH, 2 mM triethylamine, 0.3 mM EDTA,
pH 9.3), and eluent B was eluent A with the alcohol content adjusted
to 45% (0.01 M sodium acetate, 45% MeOH, 2 mM triethylamine, 0.3
mM EDTA, pH 9.3). Measurement of amino acid concentrations
needed a precolumn derivatization (fixation of a fluorophore to the
sample to produce fluorescent derivatives) with an ortho-phthaldial-
dehyde (OPA) reagent (37 mM OPA, 128 mM 2-mercaptoethanol,
25% methanol, water, 24 mM borax, pH 10) mixed online and added
to the dialysate (vol/vol). Glutamate, glutamine, aspartate, and aspar-
agine were analyzed.
Catecholamine determination. Dopamine extracellular levels in
brain dialysates were measured with HPLC coupled to an electro-
chemical detector (Decade II, Antec, Leyden, The Netherlands) work-
ing at 720 mV and 20 pA, an automatic injector (Triathlon, Spark),
and an AZUR software integrator. The pump (Shimadzu, LC-1 OAD
VP) delivered the mobile phase at 0.37 ml/min into a reverse-phase
C18 column (3.2 ⫻ 200 mm ID, particle size 3 ␮m, Phymep) warmed
at 30°C. The mobile phase consisted, for 1,000 ml, of 5 g of citric
acid, 15 g of dipotassium hydrogen orthophosphate (K2HPO4), 0.13 g
EDTA, 3.5 ml of triethylamine (Sigma, St-Quentin Fallavier, France),
and 1.7 mg of heptan-sulfonic acid in 1:1 of HPLC-grade water
(Sigma; Carlo Erba, Italy) completed by 200 ml of methanol (Merck)
and 30 ml of tetrahydrofurane (Merck). Final pH was adjusted to 4.2
with acetic acid.
DOPAC and HVA were measured with HPLC coupled to an
amperometric detector (Eldec 105, Precision Instrument). The glassy
carbon electrode was at ⫹650 mV against an Ag/AgCl reference
electrode. A 1-␮l sample was injected into a reverse-phase C18
column (3.2 ⫻ 200 mm ID, particle size 3 ␮m, Phymep). The same
mobile phase was delivered at 0.3 ml/min by a Bio-Teck Kontron 525
pump.
Statistical Analysis
For each subject, baseline was determined using the four samples
preceding gas pressure exposure. Samples were next expressed as a
percentage of baseline, taken as the 100% value (baseline). Data for
the whole group were noted using median value and the 25th to 75th
percentiles. Nonparametric statistical tests were used as the number of
animals was small. First, baseline groups were compared with the
compression and exposure stages for each experiment type and each
molecule, with a Kruskal-Wallis test followed by a Dunn test. Then
the effects of NMDA infusion were compared under nitrogen expo-
sure and in atmospheric conditions for each molecule development,
and at each time point (Mann-Whitney test).
Exposure during compression time (from 0.01 MPa to 3 MPa) was
differentiated from the stay at maximal pressure period (3 MPa).
RESULTS
No rat died because of the surgery. Twenty of 35 of the rats
previously surgically implanted presented a complete sequence of
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 INERT GAS VERSUS GLUTAMATE RELEASE
dialysates exploitable by HPLC. Others experiments failed be-
cause of unanalyzable dialysates (n ⫽ 6 in hyperbaric conditions)
with the HPLC (too low sensitivity), or because of the rat behavior
[hyperexcitability (n ⫽ 5) or rat lying on the back (n ⫽ 4)] that
was incompatible with the fragility of the microdialysis devices.
The probe implantation was verified after each experiment.
Behavioral Observations
The behavioral signs observed in rats submitted to NMDA
infusion at atmospheric pressure differed from those exposed
to NMDA and to nitrogen under pressure.
Under atmospheric conditions and during the microdialysis
control period, the rats of the different groups did not show any
behavioral alterations. Under atmospheric conditions and during
the NMDA infusion, rats (n ⫽ 8) showed motor and locomotor
hyperactivity due to the hyperexcitability of the central nervous
system. There was no alteration of the righting reflex.
Under nitrogen at 3 MPa, without (n ⫽ 6) or with NMDA
infusion (n ⫽ 6), motor and locomotor disturbances, uncoordi-
nated movements, ataxia and some stereotyped activities were
visually observed. The animals staggered before falling and lying
on one side. Nitrogen at 3 MPa impaired an animal’s ability to
right itself. No sign of hyperexcitability stage occurred.
Neurochemical Study
In rat striatum, during the control period, the medium con-
centrations of glutamate, aspartate, glutamine, and asparagine
were, respectively, 1.87 ⫾ 0.85, 0.33 ⫾ 0.16, 109.87 ⫾ 40.21,
0.54 ⫾ 0.09 ␮M. Concerning monoamines, the medium concen-
tration of dopamine was 8.19 ⫾ 6.94 nM, and those of DOPAC
and HVA were, respectively, 0.61 ⫾ 0.57 and 0.43 ⫾ 0.62 ␮M.
The NMDA infusion under atmospheric conditions (0.01
MPa) significantly increased striatal levels of the four amino
acids studied here: glutamate, aspartate, glutamine, and
1953
asparagine (Table 1). The same infusion conducted under
nitrogen at 3 MPa revealed significant lower levels of these
amino acids (Table 2). In opposition, the NMDA-induced
effects on monoamine levels were statistically not affected
by the nitrogen at 3 MPa exposure (Table 3). More details
on each molecule follow.
Extracellular Glutamate Levels
Under atmospheric conditions (0.01 MPa), and compared
with baseline, NMDA infusion increased extracellular gluta-
mate levels from the beginning to the end of the experiment
(Table 1 and Fig. 1A). The increase of glutamate averaged
241.8%, compared with baseline, and the maximum value was
717.6%.
Under nitrogen at 3 MPa, and compared with baseline,
extracellular glutamate levels decreased from the compression
stage to the end of the 3 MPa period (Table 1 and Fig. 1A). The
average decrease in glutamate reached 10.2% during the com-
pression stage, and 23.6% during the maximal nitrogen pres-
sure exposure (Fig. 1A).
When both conditions were combined, NMDA retrodialysis
and high pressure of nitrogen, extracellular glutamate levels
remained unchanged from the compression stage to the end of
the 3 MPa period (Table 1 and Fig. 1A).
Glutamate levels were significantly higher when compar-
ing values recorded during NMDA infusion in the atmo-
spheric pressure group to those recorded during nitrogen
exposure with NMDA, or to those recorded during nitrogen
exposure alone (Table 2). The intergroup comparisons (Ta-
ble 2) highlighted no significant difference between the
nitrogen exposure group and the nitrogen at 3 MPa plus
NMDA group.

Table 1. Intragroup comparison of striatal amino acid baselines against their developments under nitrogen at 3 MPa
(n ⫽ 6), or under atmospheric pressure with NMDA retrodialysis (n ⫽ 8), or under nitrogen exposure with NMDA
retrodialysis (n ⫽ 6)

Baseline Nitrogen at 3 MPa NMDA at 0.01 MPa Nitrogen at 3 MPa ⫹ NMDA

Control at 0.01 MPa Stay at 3 MPa Stay at 0.01 MPa Stay at 3 MPa
Comp Median (1st, 3rd quartile) Comp Median (1st, 3rd quartile) Comp Median (1st, 3rd quartile)
Median (1st, 3rd
Amino Acid quartile) P value P value Post hoc test P value P value Post hoc test P value P value Post hoc test

76.5 (64.5, 86.9) 241.8 (435.3, 747.2) 64.9 (45.6, 133.4)

Glutamate 99.7 (95.9, 109.0) 0.006 䊐■ <0.001 䊐䊐䊐䊐䊐■■■■ <0.001 䊐■ <0.001 ■■■■■■■■■ 0.297 䊐䊐 0.224 䊐䊐䊐䊐䊐䊐䊐䊐䊐

62.7 (57.6, 79.4) 108.3 (104.0, 115.9) 104.1 (46.4, 169.7)

Glutamine 100.5 (95.5, 110.1) <0.001 䊐■ <0.001 䊐䊐■䊐䊐■■■■ 0.528 䊐䊐 <0.001 ■■䊐■■■■■■ 0.251 䊐䊐 0.983 䊐䊐䊐䊐䊐䊐䊐䊐䊐

98.3 (85.6, 113.3) 292.5 (195.9, 530.4) 81.6 (41.4, 150.2)

Aspartate 102.2 (88.2, 110.8) 0.866 䊐䊐 0.427 䊐䊐䊐䊐䊐䊐䊐䊐䊐 0.019 䊐■ <0.001 䊐䊐䊐䊐䊐䊐䊐䊐䊐 0.253 䊐䊐 0.138 䊐䊐䊐䊐䊐䊐䊐䊐䊐

81.6 (71.2, 103.2) 195.3 (140.1, 289.6) 110.2 (79.1, 373.7)

Asparagine 99.1 (93.6, 108.5) 0.742 䊐䊐 0.019 䊐䊐䊐䊐䊐䊐䊐■䊐 0.011 䊐■ <0.001 ■■■■■■■■■ 0.122 䊐䊐 0.981 䊐䊐䊐䊐䊐䊐䊐䊐䊐
Baselines and periods at maximal pressure [but not the compression (Comp) stage] were described using median values, with the 25th and 75th
percentiles in parentheses. Each baseline was compared with compression stage (ⱕ3 MPa) and compared with a maximum pressure period (3 MPa) using
a Kruskal-Wallis test (P values were noted, ␣ ⫽ 5%), followed by a post hoc test transcribed by squares. Each square represents a string of samples
(⬃median value) that have to be compared with the baseline samples, arranged in chronological order: 2 squares for 2 series of samples available during
the compression stage (or similar); 9 squares for 9 series of samples available during the stay at the maximal pressure (or similar). Dark squares indicate
a significant difference, as pointed out by a post hoc Dunn test (␣ ⫽ 5%), between samples at the corresponding time point and its baseline. White squares
indicate no significant difference between the string of samples at the corresponding time point and the baseline. NMDA, N-methyl-D-aspartate. Boldface
P values are significant.

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1954 INERT GAS VERSUS GLUTAMATE RELEASE

Table 2. Intergroup comparison of amino acid Extracellular Aspartate Levels

developments, under nitrogen at 3 MPa (n ⫽ 6) and under
atmospheric pressure with NMDA retrodialysis (n ⫽ 8), and Under atmospheric conditions, and compared with baseline,
under nitrogen exposure with NMDA retrodialysis (n ⫽ 6) NMDA infusion increased extracellular aspartate levels from
the beginning to the end of the experiment (Table 1), with a
Nitrogen vs. Nitrogen ⫹ NMDA Nitrogen ⫹ NMDA maximum up to 467% (Fig. 1C). Under nitrogen at 3 MPa,
NMDA vs. Nitrogen vs. NMDA with or without NMDA, aspartate levels remained unchanged
Comp 3 MPa Comp 3 MPa Comp 3 MPa compared with the baseline (Table 1 and Fig. 1C). Actually,
Amino Acid P value P value P value P value P value P value the nitrogen exposure groups have shown no significant dif-
Glutamate <0.001 <0.001 0.624 0.282 0.462 <0.001 ference between them (Table 2). We recorded significantly
Glutamine <0.001 <0.001 0.734 0.007 1.000 0.805 higher levels of aspartate in the NMDA infusion in the atmo-
Aspartate 0.041 <0.001 0.521 0.250 0.946 <0.001 spheric pressure group than in the both nitrogen at 3 MPa
Asparagine 0.047 <0.001 0.910 <0.001 0.713 0.004 groups (Table 2).
The compression stages (ⱕ3 MPa) and the maximal pressure period (3 MPa)
of all groups were compared against each other, using a Kruskal-Wallis test Extracellular Asparagine Levels
(␣ ⫽ 5%). P values were noted. Boldface P values are significant.
NMDA alone increased striatal asparagine levels from the
beginning to the end of its administering (Table 1 and Fig. 1D).
Extracellular Glutamine Levels Increase in asparagine levels averaged 195.3% compared with
baseline, and the maximum value was 238.8%.
NMDA infusion significantly increased extracellular glu- The medium level of asparagine was decreased by 18.2%
tamine levels, under atmospheric conditions, in the second part when rats were submitted to the maximal pressure of nitrogen
of the experiment (Table 1 and Fig. 1B). Glutamine levels (Table 1 and Fig. 1D).
increased up to 108.3%, on average, compared with baseline, The combination of NMDA and nitrogen at 3 MPa induced
and the maximum value was 172.5%. no change in extracellular asparagine levels compared with
Under nitrogen at 3 MPa, and compared with baseline, extra- baseline (Table 1 and Fig. 1D).
cellular glutamine levels decreased from the compression stage to NMDA alone, in atmospheric conditions, induced the most
the end of the 3 MPa period (Table 1 and Fig. 1B). Decrease in important increase, on average, in asparagine levels. It was
glutamine averaged 17.6% during the compression stage, and statistically more important than when the NMDA has been
37.3% during the maximal nitrogen pressure period (Fig. 1B). applied under nitrogen pressure (Fig. 1D and Table 2). The
smallest asparagine levels in the striatum were recorded with
Under nitrogen at 3 MPa with NMDA retrodialysis, and
nitrogen at 3 MPa only (Fig. 1D and Table 2).
compared with baseline, no change in extracellular glutamine
was recorded (Table 1 and Fig. 1B).
Extracellular Dopamine Levels
Glutamine level was significantly lower when comparing
values recorded during nitrogen exposure only to those re- The NMDA infusion under atmospheric conditions in-
corded during NMDA infusion whatever the pressure (Fig. 1B creased extracellular dopamine levels from the beginning to the
and Table 2). No significant difference was found between the end of the experiment (Table 3 and Fig. 2A). Dopamine levels
nitrogen at 3 MPa plus NMDA group and NMDA infusion in reached a medium value of 242.9%. The maximum value was
atmospheric pressure group (Table 2). 991.5%.

Table 3. Comparison of striatal monoamine baselines with their developments under atmospheric pressure with NMDA
retrodialysis (n ⫽ 8), and under nitrogen exposure with NMDA retrodialysis (n ⫽ 6)
NMDA at 0.01 MPa Nitrogen at 3 MPa ⫹ NMDA
Nitrogen ⫹ NMDA
0.01 MPa 3 MPa vs. NMDA
Baseline
Comp Median (1st, 3rd quartile) Comp Median (1st, 3rd quartile)
Control at 0.01 MPa Comp 3 MPa
Monoamine Median (1st, 3rd quartile) P value P value Post hoc test P value P value Post hoc test P value P value

242.9 (116.4, 546.4) 302.9 (154.6, 855.0)

Dopamine 100.0 (81.8, 116.5) <0.001 ■■ <0.001 ■■■■■■䊐䊐䊐 0.108 䊐䊐 <0.001 ■■■■■■■■■ 0.291 0.175

88.7 (68.9, 103.4) 88.0 (71.4, 191.8)

DOPAC 99.4 (77.5, 110.7) 0.242 䊐䊐 0.362 䊐䊐䊐䊐䊐䊐䊐䊐䊐 0.502 䊐䊐 0.977 䊐䊐䊐䊐䊐䊐䊐䊐䊐 0.540 0.256

38.8 (31.1, 46.5) 36.8 (32.1, 63.0)

HVA 99.9 (86.6, 110.8) 0.011 䊐■ <0.001 ■■■■■■■■■ 0.013 ■■ 0.004 䊐■■■■■䊐■■ 0.066 0.420
Baselines and maximal pressure periods (but not the compression stage) were described using median values, with 25th and 75th percentiles in parentheses.
Each baseline was compared with its compression stage (ⱕ3 MPa) and compared with the maximal pressure period (3 MPa) using a Kruskal-Wallis test (P values
were noted, ␣ ⫽ 5%), followed by a post hoc test transcribed by squares. Each square represents a string of samples (⬃median value) that have to be compared
with the baseline samples, arranged in chronological order. Dark squares indicate a significant difference, as pointed out by a post hoc Dunn test (␣ ⫽ 5%),
between samples at the corresponding time point and its baseline. White squares indicate no significant difference between the string of samples at the
corresponding time point and the baseline. Boldface P value are significant.

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Fig. 1. A–D: effects of NMDA infusion under normobaric (n ⫽ 8) and high (n ⫽ 6) nitrogen-oxygen pressure atmospheres on levels of extracellular amino acids
(A: glutamate; B: glutamine; C: aspartate; D: asparagine) in rat striata. The ordinate of each graph shows the level of amino acid expressed as the percentage
of the baseline level, which is the mean of the 4 consecutive values observed immediately before the beginning of the compression/infusion of NMDA (2 mM).
The time of compression (or similar) is shown by the gray area, which is followed by the maximal pressure period, 3 MPa (or similar). Dotted lines mark
experiments conducted under nitrogen at 3 MPa. Dotted lines with dashes mark experiments using NMDA retrodialysis in the striatum under atmospheric
pressure. Solid lines mark experiments using NMDA retrodialysis under nitrogen at 3 MPa. Intergroup comparisons: large symbols in top left corners of graph
indicate significant change in development of amino acid levels (␣ ⫽ 0.05, Kruskal-Wallis test) between the NMDA-nitrogen group and the NMDA-atmospheric
group (§), between the NMDA-atmospheric group and the nitrogen group (*), and the nitrogen group and the NMDA-nitrogen group (#). Each point is the
median; the 25th–75th percentiles are not represented to avoid confusion. Individual time points: small symbols indicate significant changes (␣ ⫽ 0.05, Dunn
test) between the NMDA-nitrogen group and the NMDA-atmospheric group (§), between the NMDA-atmospheric group and the nitrogen group (*), and the
nitrogen group and the NMDA-nitrogen group (#) at the corresponding time point.

The same infusion conducted under 3 MPa of nitrogen
increased extracellular dopamine levels up to an average value
of 276.4%, during the maximal pressure period (Table 3 and
Fig. 2A). The dopamine peak corresponded to 858.2%.
The comparison between these two developments did not
reveal significant differences.
Extracellular DOPAC Levels
Neither under atmospheric conditions nor nitrogen at 3 MPa
did NMDA infusion induce changes in extracellular DOPAC
levels compared with its baseline (Table 3 and Fig. 2B).
The comparison between these two developments did not
show significant differences, which leads to the conclusion that
the same pattern can be observed between the control experi-
ment and the nitrogen exposure group (Table 3).
Extracellular HVA Levels
The NMDA infusion, applied under atmospheric conditions,
significantly decreased (61.2% on average) striatal HVA levels
between the control period and the remainder of protocol
compared with baseline (Table 3). HVA levels were decreased
from the start, by 43.7% in the first 20 min, to the end, by
62.3% in the last minutes (Fig. 2B).
Under nitrogen at 3 MPa with NMDA retrodialysis, the
development was the same as under atmospheric conditions, as
no significant differences were observed in the comparison of
these two developments (Table 3). A significant decrease
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occurred, under nitrogen at 3 MPa with the NMDA retrodialy-
sis, from the time of compression (⫺57.2%) to the end of the
maximal nitrogen pressure period (⫺67.0%) (Fig. 2B).
DISCUSSION
Levels of dopamine and glutamate recorded in the striatum
under pressure of nitrogen are in accordance with our previous
laboratory studies (43). Under nitrogen narcosis, extracellular
glutamate, glutamine, and asparagine levels in the striatum
were recorded, and no change in aspartate development was
observed (43). Balon et al. (3), Dedieu et al. (17), and Lavoute
et al. (24) have reported a decrease in striatal dopamine level.
Our present results complete those of previous studies and
confirm the action of NMDA on its glutamatergic receptor.
Under atmospheric conditions, NMDA-Receptor stimulation
by NMDA retrodialysis in the striatum induces increases in
dopamine and glutamate in this structure. This is a good
evidence for interactions between these transmitters. NMDA
retrodialysis also involves an increase in glutamine, aspartate
and asparagine levels, and a decrease in DOPAC and HVA
levels under atmospheric conditions.
The interactions between glutamate and dopamine disappear
under nitrogen narcosis. Indeed nitrogen at 3 MPa did not
change the increase of dopamine induce by striatal NMDA
infusion but suppressed the increase of glutamate, glutamine,
aspartate, and asparagine and the decrease of DOPAC levels.
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1956 INERT GAS VERSUS GLUTAMATE RELEASE
Fig. 2. A and B: effects of NMDA infusion under normobaric (n ⫽ 8) and high
(n ⫽ 6) nitrogen-oxygen pressure atmospheres on levels of extracellular
monoamines [A: dopamine; B: dihydrophenylacetic acid (DOPAC) and ho-
movanillic acid (HVA)] in rat striata. The ordinate of each graph shows the
level of monoamine expressed as the percentage of the baseline level, which is
the mean of the 4 consecutive values observed immediately before the
beginning of the compression/infusion of NMDA (2 mM). The time of
compression (or similar) is shown by the gray area, which is followed by the
maximal pressure period, 3 MPa (or similar). Dotted lines with dashes mark
experiments using NMDA retrodialysis in the striatum under atmospheric
pressure. Solid lines mark experiments using NMDA retrodialysis under
nitrogen at 3 MPa. Intergroup comparison show no significant change in
development of monoamine levels (␣ ⫽ 0.05, Kruskal-Wallis test) between the
NMDA-nitrogen group and the NMDA-atmospheric group. Each point is the
median; the 25–75th percentiles are not represented to avoid confusion. For
individual time point, there was no significant change (␣ ⫽ 0.05, Dunn test)
between the NMDA-nitrogen group and the NMDA-atmospheric group at the
corresponding time point.
Nitrogen has no effect on the NMDA-induced decrease in
HVA levels.
First these results indicate that NMDA receptors remain
functional under nitrogen narcosis, as NMDA infusion signif-
icantly potentiates dopamine increase. Second, they show that
there is no more NMDA-induced interaction between gluta-
mate and dopamine under nitrogen pressure. The activation of
the NMDA receptor in the striatum is not sufficient to increase
extracellular concentration of glutamate under nitrogen expo-
sure. Balon et al. (3) and Lavoute et al. (26) have also reported
the inversion of striatal dopamine release by NMDA injection
in the substantia nigra pars compacta; they also conclude that
NMDA-Receptor was not affected by nitrogen at pressure.
NMDA and Basal Ganglia Pathways
The dichotomy between glutamate and dopamine develop-
ments points to the conclusion that the feedback/forward path-
way controls in basal ganglia (20, 31–33, 39, 40) are disrupted
under nitrogen pressure.
Dopamine pathway. Dopamine cells follow the same devel-
opments after NMDA stimulation, whether under nitrogen
exposure or not. Dopamine cells seem to be resistant to
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nitrogen narcosis, whereas glutamatergic cells are affected
directly or indirectly. Dopamine axon terminals in the striatum
are relatively insensitive to a variety of glutamate agonists (6,
15, 29, 44). The striatal action of NMDA on nigrostriatal
dopaminergic neurons is not more clearly established (2, 8, 9,
11, 12, 23, 27, 29). Under atmospheric conditions, Marti et al.
(28) suggested that NMDA-induced dopamine increase ap-
pears to be a result of the activation of the striatonigral
pathway. Indeed, in this study, this means that GABAergic
cells of the striatonigral pathway are thus not directly inhibited
by nitrogen under pressure. Lavoute’s findings (26) support
these suggestions.
Glutamate pathway. Glutamate level, which is decreased
under nitrogen narcosis, cannot be restored by the activation of
striatal NMDA receptor.
According to Marti et al. (28), NMDA-evoked striatal
glutamate release is mediated by the activation of striatofu-
gal GABAergic neurons and requires dopamine receptor
activation. The same team also claims that striatal glutamate
release evoked by NMDA is a result of the disinhibition of
thalamostriatal and corticostriatal glutamatergic projections.
Indeed, the striatal glutamate decrease described in our work
would plead in favor of a disturbance at the level of
thalamostriatal and corticostriatal glutamatergic projections,
but not in GABAergic striatofugal cell disturbances as we
can still observe a striatal dopamine increase related to these
cells (see above).
This does not exclude that NMDA stimulation induces
striatal dopamine increase, and dopamine remains necessary to
modulate striatal glutamate release evoked by NMDA (10).
Metabolite Interpretation
According to Dedieu et al. (17), DOPAC and HVA metab-
olisms should be enhanced by nitrogen exposure, and dopa-
mine should be decreased. DOPAC is generated from dopa-
mine within dopaminergic nerve terminals by monoamine
oxidase (MAO). HVA is produced from extracellular dopa-
mine and DOPAC by catechol-O-methyltransferase (COMT)
(18). Although there is an increase in NMDA-induced dopa-
mine, no change was observed in its degradation into DOPAC.
The HVA decrease could indicate a downregulation of the
COMT induced by the NMDA infusion. Indeed, the dopamine
increase, in part, could result from a nondegradation of itself.
Glutamine and asparagine are the metabolic precursors of
glutamate (16, 21) and aspartate (22, 30, 35), respectively.
They can be considered as an indicator of their metabolism.
Here it was demonstrated that NMDA infusion was effective to
increase glutamate, aspartate, and their metabolites levels un-
der atmospheric conditions. However, this method failed to
increase them under nitrogen exposure. Indeed, concomitant
failures in effluxes of glutamine and asparagine suggest that the
decrease of glutamate and aspartate can be of metabolic origin
(33). Moreover, the release of aspartate, the cotransmitter of
glutamate, is also thought to be of metabolic origin (20, 33).
Hence, the failure, under nitrogen narcosis, in the NMDA-
induced aspartate increase can be attributed to the effect of the
gas on metabolic mechanisms.
The neurochemical study performed on metabolites indi-
cates that nitrogen under pressure does not affect the vesicular
neurotransmitter release alone. Indeed the neurotransmitter
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 INERT GAS VERSUS GLUTAMATE RELEASE
synthesis, uptake, or degradation should also be affected by
nitrogen under pressure.
Behavior and Neurotransmission
These different neurochemical changes highlighted with
NMDA, whether under nitrogen pressure or not, could partly
explain the motor and locomotor behavior disruptions under
nitrogen narcosis. The increase of motor and locomotor activ-
ity that occurs with the NMDA infusion under atmospheric
condition can be attributed to the increase of dopamine and
glutamate levels. Hence, the decreased activity observed under
nitrogen pressure, even with NMDA receptor stimulation,
seems to be related to the decrease in glutamate (and aspartate)
level, as dopamine level was shown to be largely enhanced
with NMDA. Nevertheless, decreased locomotor activity, se-
dation, and motor disturbances under nitrogen-oxygen pres-
sure, previously reported by Balon et al. (3), can be attributed
to a decrease of dopamine levels (4). It confirms that both
dopamine and glutamate are keys in nitrogen narcosis behav-
ior.
Conclusion
In conclusion, the viability of the NMDA receptor is not
directly affected by nitrogen under pressure. The NMDA-
evoked glutamate increase is counteracted by nitrogen narco-
sis. On the other hand, the NMDA-induced dopamine increase
is not affected by the high pressure of nitrogen. Nevertheless,
no improvement in motor and locomotor disturbances was
observed with high striatal concentration in dopamine. Using
the retrodialysis technique in nitrogen narcosis, we show for
the first time dissociation between glutamate and dopamine
pathways of basal ganglia. Indeed, the study of both dopamine
and glutamate at the same time should be considered system-
atically to better improve the neurochemical disorders of ni-
trogen narcosis. Moreover, troubles of the glutamatergic re-
lease are also coupled to disturbances in glutamine aspartate
and asparagine levels in the striatum. Subsequent experiments
have to be done to specify what properties make the striatal
glutamate pathways sensitive to nitrogen under pressure.
ACKNOWLEDGMENTS
We thank the following people, all from UMR-MD2 laboratories, for
valuable contributions to this work: Myriam Nicolas and Boualem Zouani,
laboratory technicians; Patrick Ledrut and Olivier Moreau, mechanics; and
Bruno Schmid, research and development technician.
GRANTS
This study was supported by Grant No. 01/0809 from the Délégation
Générale pour l’Armement, Paris, France.
DISCLOSURES
No conflicts of interest are declared by the authors.
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