Examination of the Role of NMDA and GABAA Receptors in the Effects of Hyperbaric Oxygen on Striatal Dopamine Levels in Rats.

Hyperbaric oxygen induced in rats a decrease in striatal dopamine levels. Such decrease could be a result of changes in glutamatergic and GABAergic controls of the dopaminergic neurons into the Substantia Nigra Pars Compacta. The aim of this study was to determine the role of gluatamatergic and Gama-Amino-Butyric-Acid neurotransmissions in this alteration. Dopamine-sensitive electrodes were implanted into the striatum under general anesthesia. After one week rest, awaked rats were exposed to oxygen-nitrogen mixture at a partial pressure of oxygen of 3 absolute atmospheres. Dopamine level was monitored continuously (every 3 min) by in vivo voltammetry with multifiber carbon electrodes before and during hyperbaric oxygen exposure. Hyperbaric oxygen induced a decrease in dopamine level in relationship with the increase in partial pressure of oxygen (-40% at 3 ATA). The used of N-Methyl-D-Aspartate, agonist of glutamatergic N-Methyl-D-Aspartate receptors did not improve considerably this change and gabazine antagonist of Gama-Amino-Butyric-Acid-a receptors induced some little alteration of this change. These results suggest the involvement of other mechanisms.

A new biophysical decompression model for estimating the risk of articular bends during and after decompression.

The biophysical models that intend to predict the risk of decompression sickness after a change of pressure are not numerous. Few approaches focus in particular on joints as target tissues, with the aim to describe properly the mechanisms inducing pain. Nevertheless, for this type of decompression incidents, called articular bends, no model proved to fit the empirical results for a broad range of exposures and decompression procedures. We present here an original biophysical decompression model for describing the occurrence of articular bends. A target joint is broken down into two parts that exchange inert gases with the blood by perfusion and with each other by diffusion over distances of a few millimetres. This diffusion pathway allows the slow amplification of microbubbles growing during and after decompression, consistent with the possible delayed occurrence of bends. The diffusion coefficients introduced into this model are larger than those introduced into most modern decompression models. Their value remains physical (#10(-9)m(2)/s). Inert gas exchanges and the formation, amplification and resorption of microbubbles during and after decompression were simulated. We used a critical gas volume criterion for predicting the occurrence of bends. A risk database extracted from COMEX experience and other published studies were used for the correlation of model parameters not known a priori. We considered a large range of exposure, and the commonly used inert gases nitrogen and helium. This correlation phase identified the worst biophysical conformations most likely to lead to the formation, in tissues such as tendons, of a large number of microbubbles recruited from pre-existing gas nuclei during decompression. The risk of bends occurrence was found to be linked to the total separated gas volume generated during and after decompression. A clamping phenomenon occurs soon after the start of decompression, greatly slowing the gas exchanges controlled especially by the oxygen window. This model, which reproduces many empirical findings, may be considered both descriptive and predictive.

A review of recent neurochemical data on inert gas narcosis.

Nitrogen narcosis occurs in humans at around 0.4 MPa (4 ATA). Hydrogen narcosis occurs between 2.6 and 3.0 MPa. In rats, nitrogen disturbances occur from 1 MPa and a loss of righting reflex around 4 MPa. Neurochemical studies in striatum of rats with nitrogen at 3 MPa (75% of anesthesia threshold) with differential pulse voltammetry have demonstrated a decrease in dopamine (DA) release by neurons originated from the substantia nigra pars compacta (SNc). Such a decrease is found also with compressed argon, which is more narcotic than nitrogen and with the anesthetic gas nitrous oxide. Inversely, compressed helium with its very low narcotic potency induces DA increase. Microdialysis studies in the striatum have indicated that nitrogen also induces a decrease of glutamate concentration. Nitrogen pressure did not modify NMDA glutamate receptor activities in SNc or striatum but enhanced GABAA receptors activities in SNc. Repetitive exposures to nitrogen narcosis suppressed the DA decrease and induced an increase. This fact and the lack of improvement of motor disturbances did not support the hypothesis of a physiological adaptation. The desensitization of the GABAA receptors on DA cells during recurrent exposures and the parallel long-lasting decrease of glutamate coupled to the increase in NMDA receptor sensitivity suggest a nitrogen neurotoxicity or addiction induced by recurrent exposures. The differential changes produced by inert gases indifferent neurotransmitter receptors would support the binding protein theory.

Dopaminergic control of striatal 5-HT level at normobaric condition and at pressure.

High pressure of helium-oxygen (He-O2) increases the extracellular levels in both serotonine and dopamine in the rat striatum. Some motor symptoms evoked by high pressure (i.e., LMA) are known to be reduced by intrastriatal infusions of D1-like (SCH23390, 1 microM) or D2-like (Sulpiride, 1 microM) dopaminergic antagonists. Other studies have also reported that serotoninergic antagonists reduce the motor perturbation at pressure. However, it remains unknown whether the changes in serotoninergic neurotransmission may contribute to the beneficial effects of intrastriatal administration of a dopaminergic antagonist. The present study reports the effects of SCH23390 and sulpiride on serotonin levels in the striatum of rats exposed to 8 MPa of He-O2. Both sulpiride and SCH23390 reduced pressure-induced striatal 5-HT increase. Our data suggest that D1-like and D2-like receptors have similar effects on a pressure-evoked striatal 5-HT increase. Thus, reduction in serotoninergic neurotransmission may be one mechanism by which dopaminergic antagonists reduce motor symptoms at pressure.

The pathway to drive decompression microbubbles from the tissues to the blood and the lymphatic system as a part of this transfer.

The formation sites of the microbubbles that are routinely detected in the bloodstream at precordial level by Doppler after a decompression are reviewed and discussed here. First, microbubbles could form on the endothelium lumen wall of the capillaries, at specific nanometric sites, but the release mechanism of such small emerging entities remains puzzling. They could be also formed from pre-existing gas nuclei present in the blood when favorable local hydrodynamic/supersaturation conditions generate microcavitation and tribonucleation phenomena. Finally, tissues could represent large pools for microbubble formation and amplification. Nevertheless, it remains to explain what the potential pathways are to drive them to the blood. Knowing that the permeability of most of the blood capillary network is quite low, an alternative is proposed for such transport. The lymphatic system, which drains the interstitial fluid to guarantee the fluid balance of tissues, could allow the transfer of micrometric elements like stabilized microbubbles formed in tissues on long distances. A final rejection in the bloodstream at the termination of both right lymphatic and thoracic ducts can be expected. The characteristics of this slow transport, activated by the muscular pump, could explain the detection on long periods of massive venous gas emboli.

Post effect of repetitive exposures to pressure nitrogen-induced narcosis on the dopaminergic activity at atmospheric pressure.

Nitrogen at pressure produces a neurological syndrome called nitrogen narcosis. Neurochemical experiments indicated that a single exposure to 3 MPa of nitrogen reduced the concentration of dopamine by 20% in the striatum, a structure involved in the control of extrapyramidal motor activity. This effect of nitrogen was explained by enhanced GABAergic neurotransmission through GABAA receptors and, to a lesser extent, by a decreased glutamatergic input to DA cells through NMDA receptors. The aim of this study was to study, under normobaric conditions, possible alterations of NMDA receptor activity in the substantia nigra pars compacta (SNc) induced by repetitive exposures to nitrogen pressure. Under general anesthesia, male Sprague-Dawley rats were implanted in the striatum with multifiber carbon dopamine-sensitive electrodes and in the SNc with guide cannulae for drug injections. After recovery from surgery, the striatal dopamine level was recorded by voltammetry in freely-moving rats, in normobaric conditions, before and after 5 repetitive exposures to 1MPa of nitrogen (threshold of nitrogen narcosis occurrence in rat). The effect of NMDA receptor activity on DA concentration was investigated using agonist (NMDA) and specific antagonist (AP7) SNc administration. Following repetitive nitrogen exposures, the ability of NMDA to elevate DA concentrations was enhanced. In contrast, after nitrogen exposure AP7 produced a paradoxical increase in DA concentration compared to its inhibitory effect before any exposure. Similar responses were obtained after a single exposure to 3MPa nitrogen. Thus, repetitive exposures to nitrogen narcosis produced a sensitization of postsynaptic NMDA receptors on DA cells, related to a decreased glutamatergic input in SNc. Consequently, successive nitrogen narcosis exposures disrupted ion-channel receptor activity revealing a persistent nitrogen-induced neurochemical change underlying the pathologic process.

Recreational Diving Practice for Stress Management: An Exploratory Trial.

Background: Within the components of Scuba diving there are similarities with meditation and mindfulness techniques by training divers to be in a state of open monitoring associated with slow and ample breathing. Perceived stress is known to be diminished during meditation practice. This study evaluates the benefits of scuba diving on perceived stress and mindful functioning. Method: A recreational diving group (RDG; n = 37) was compared with a multisport control group (MCG; n = 30) on perceived stress, mood, well-being and mindfulness by answering auto-questionnaires before and after a 1-week long UCPA course. For the diving group, stability of the effects was evaluated 1 month later using similar auto-questionnaires. Results: Perceived stress did not decrease after the course for the MCG [ The divers showed a significant reduction on the perceived stress score (p < 0.05) with a sustainable effect (p = 0.01)]. An improvement in mood scale was observed in both groups. This was associated to an increase in mindfulness abilities. Conclusions: The practice of a recreational sport improves the mood of subjects reporting the thymic benefits of a physical activity performed during a vacation period. The health benefits of recreational diving appear to be greater than the practice of other sports in reducing stress and improving well-being.

Recent neurochemical basis of inert gas narcosis and pressure effects.

Compressed air or a nitrogen-oxygen mixture produces from 0.3 MPa nitrogen narcosis. The traditional view was that anaesthesia or narcosis occurs when the volume of a hydrophobic site is caused to expand beyond a critical amount by the absorption of molecules of a narcotic gas. The observation of the pressure reversal effect on general anaesthesia has for a long time supported the lipid theory. However, recently, protein theories are in increasing consideration since results have been interpreted as evidence for a direct anaesthetic-protein interaction. The question is to know whether inert gases act by binding processes on proteins of neurotransmitter receptors. Compression with breathing mixtures where nitrogen is replaced by helium which has a low narcotic potency induces from 1 MPa, the high pressure nervous syndrome which is related to neurochemical disturbances including changes of the amino-acid and monoamine neurotransmissions. The use of narcotic gas (nitrogen or hydrogen) added to a helium-oxygen mixture, reduced some symptoms of the HPNS but also had some effects due to an additional effect of the narcotic potency of the gas. The researches performed at the level of basal ganglia of the rat brain and particularly the nigro-striatal pathway involved in the control of the motor, locomotor and cognitive functions, disrupted by narcosis or pressure, have indicated that GABAergic neurotransmission is implicated via GABAa receptors.

Effects of NMDA administration in the substantia nigra pars compacta on the striatal dopamine release before and after repetitive exposures to nitrogen narcosis in rats.

Hyperbaric nitrogen-oxygen exposure developed in rats a decrement of the striatal dopamine release, which was reversed by repetitive exposures. This dopamine decrease could be the result of the antagonistic effect of nitrogen on NMDA receptors. The increment of the dopamine release, following repetitive exposures to nitrogen, could be attributed to a desensitisation of NMDA receptors to the effects of nitrogen. To test these hypotheses, male Sprague-Dawley rats were implanted with electrodes in the striatum to measure dopamine release by voltammetry and cannula in the substantia nigra pars compacta for NMDA injection. Free-moving rats were exposed up to 3MPa of nitrogen-oxygen mixture before and after 5 exposures to 1MPa. At the first exposure to 3MPa, the dopamine level decreased (-15%) but is counteracted by NMDA administration. In contrast, after repetitive exposure, the second exposure to 3MPa, induces a 10% dopamine increase. NMDA administration significantly potentiated this increase. Our results neither support the hypothesis of an antagonist effect of nitrogen on NMDA receptors at the first exposure, nor that of a NMDA receptor desensitization following repetitive exposures to hyperbaric nitrogen.

Gamma-aminobutyric acid and the high pressure neurological syndrome.

Sodium valproate, nipecotic acid, diaminobutyric acid (DABA) and beta-alanine are drugs which enhance transmission mediated by gamma-aminobutyric acid (GABA) by a variety of mechanisms. They were used to study the role of GABA in the high pressure neurological syndrome (HPNS) in the rat. Sodium valproate, nipecotic acid and DABA reduced the increase in slow waves seen in the electroencephalogram (EEG) of control rats at pressures above 10-20 ATA; however, only sodium valproate had a beneficial effect on the behavioural signs of the high pressure neurological syndrome (tremor, myoclonus and convulsions). Sodium valproate is also thought to decrease neurotransmission produced by excitatory amino acids; thus, these results suggest that GABA is not one of the major neurotransmitters involved in all aspects of the high pressure neurological syndrome and that changes in excitatory neurotransmission may affect the behavioural signs.

Pressure reversed extracellular striatal dopamine decrease produced by D1 receptor agonist SKF 38393, and D2 receptor agonist LY 171555, but failed to change the effect of the activation of both D1 and D2 receptors.

When human divers or experimental animals are exposed to high pressure, they develop the high-pressure neurological syndrome which is characterized by electroencephalographic changes, and behavioral disturbances. Recently, neurochemical disorders such as a pressure-induced increase in dopamine release have been demonstrated. In the present study, pharmacological experiments, using dopamine receptor agonists such as D1 receptor agonist SKF 38393, D2 receptor agonist LY 171555, and D1/D2 receptor agonist apomorphine, were performed to investigate dopamine receptor function at the neurochemical level. Only apomorphine and mixed SKF 38393 + LY 171555 prevented the pressure-induced increase in dopamine release while SKF 38393 or LY 171555 administered alone failed to do so. The results suggest that the D1-D2 link would be reduced under high pressure because of an abnormal function of D1 receptors which would allow high-affinity D2 states for dopamine. If so, such a preponderance of high-affinity states in D2 postsynaptic receptors could be associated with hyperbaric hyperlocomotor activity. Elsewhere, results also suggested that the pressure-induced disorders in dopamine receptor function could be involved in the pressure-induced elevation in dopamine release.

Dopamine increase in the nucleus accumbens of rats exposed to high pressure.

When human divers and experimental animals are exposed to high pressure, they develop the high pressure neurological syndrome (HPNS) characterized by electroencephalographic changes, sleep and behavioral disturbances. Free-moving rats chronically implanted in the nucleus accumbens with carbon electrodes essentially selective to dopamine (DA) were compressed to 80 bar. Compression was found to lead to a sustained increase in extracellular DA level (+88%), then during the stay and decompression phases, values progressively decreased. These results are discussed in the field of the involvement of the DA meso-limbic pathways in the occurrence of some of the behavioral disturbances of HPNS in rats including hyperlocomotor activity and hoarding behavior.

Contribution of central 5-HT2 receptors in the occurrence of locomotor activity and myoclonia in freely moving rats exposed to high pressure.

Helium pressure of more than 20 bar is a well known cause of neuroexcitatory changes, referred to as the high pressure neurological syndrome. In rodents, symptoms include myoclonia and locomotor activity. In the present study, we used the 5-HT2A receptor antagonist ketanserin and the 5-HT2C receptor agonist m-CPP to investigate the role of central 5-HT2 receptors in the occurrence of these symptoms. Results suggest that 5-HT2A receptors and 5-HT2C receptors would play a crucial role in the development of myoclonia and locomotor activity, respectively. The selectivity of the drugs used, and the central origin of both myoclonia and locomotor activity are discussed.

Administration of either non-NMDA receptor agonists or NMDA receptor antagonists into the substantia nigra or the globus pallidus reduces the psychostimulant effect of high helium pressure on locomotor activity in rats.

Helium pressure of >2 MPa is a well known factor underlying pressure-dependent central neuroexcitatory disorders that include locomotor and motor activity (LMA) and myoclonia. We investigated the effects of bilateral injection in either the substantia nigra (SN) or the globus pallidus (GP) of the AMPA receptor agonist (+/-)AMPA, the kainate receptor agonist kainic acid, the NMDA receptor agonist (+/-)-cis-piperidine-2,3-dicarboxylic acid (PDA), and the NMDA receptor antagonist (+/-)-2-amino-7-phosphono-heptanoic acid (AP-7) in the occurrence of helium pressure-induced LMA and myoclonia. Administration of AMPA, kainate, or AP-7 in either the SN or the GP significantly reduced high helium pressure-induced LMA, whereas the NMDA receptor agonist showed no significant effect. Injection in the SN of the non-NMDA receptor agonist AMPA and the NMDA receptor agonist PDA increased the development of high helium pressure-induced myoclonia, whereas injection of the NMDA receptor antagonist AP-7 into the SN or the GP decreased it. This confirms that NMDA transmission in the SN and the GP would play a major role in the development of helium pressure-induced LMA; manipulation of AMPA and kainate systems may have therapeutic potential. The opposite effects of AMPA on LMA and myoclonia also confirm the neural substrates involved in the motor disorder produced by helium pressure differ substantially between LMA and myoclonia.

Pressure increases de novo synthesized striatal dopamine release in free-moving rats.

When human divers or experimental animals are exposed to high pressure, they develop brain and biobehavioural disorders. Since it has been demonstrated that pressure exposure increased striatal DA release, the present experiments were intended to investigate whether it resulted from a release in de novo synthesized DA or from a release of DA stores. Free-moving rats implanted with multi-fibre carbon electrodes sensitive to DA were pretreated with reserpine, a depleter of catecholamine stores, and compressed to 8 MPa. Results show that pretreatment with reserpine had no ability to block the pressure-induced DA release. In the light of previous relevant studies, we suggested that the elevation of DA release under high pressure would be the consequence of a release in de novo synthesized DA.

Modulation by GABA transmission in the substantia nigra compacta and reticulata of locomotor activity in rats exposed to high pressure.

Helium pressure of > 20 bar causes neuroexcitatory changes referred to as the high pressure neurological syndrome. In rodents, symptoms include locomotor and motor activity (LMA), myoclonia and, at greater pressure, convulsions. We studied the effects of the GABA reuptake inhibitor nipecotic acid, the GABA transaminase inhibitor gamma-vinyl-GABA (GVG), the GABAA receptor agonist muscimol, and the GABAB receptor agonist baclofen. Whatever the drug used, bilateral administration in the substantia nigra reticulata (SNR) or in the substantia nigra compacta (SNC) showed no significant effects on myoclonia. In contrast, administration in the SNR of nipecotic acid, GVG, and baclofen resulted in a significant decrease of LMA; administration of muscimol in the SNR increased LMA. No significant effect was seen when drugs were injected in the SNC. These results suggest that changes in GABA transmission in the SNR, but not in the SNC, play a crucial role in the control of motor activity and the regulation of movement.

Effects of high pressures of various gas mixtures on rat striatal dopamine detected in vivo by voltammetry.

This work was performed to study the effect of pressure of various gas breathing mixtures on dopaminergic activity in the striatum by in vivo differential pulse voltammetry using carbon multifiber electrodes chronically implanted in 23 freely moving rats. Compression (0.5 bar/min) in a helium-oxygen mixture induced an increase in striatal extracellular dopamine (DA) beginning at 10-20 bars and reaching 32% above precompression levels when arriving at 90 bars (n = 9). To demonstrate that this increase is dopaminergic, nine rats with right nigrostriatal pathway 6-hydroxydopamine lesions were compressed in the same conditions. In this case, the increase in DA did not occur in the right caudate nucleus but was recorded in the intact left caudate nucleus. To study the effects on DA increase of narcotic gases, which are known to reduce some high-pressure nervous syndrome symptoms, eight and six rats were compressed in helium-nitrogen-oxygen and hydrogen-helium-oxygen mixtures, respectively. They produced similar changes in striatal DA level in the same pressure range (23 and 20% increase, respectively, at the end of the compression). Consequently, the increase in striatal DA seems independent of the nature of the breathing mixture and seems related to the increase of pressure. The origin of this increase could be a pressure effect at the pre- or postsynaptic level.

Pressure-induced striatal dopamine release correlates hyperlocomotor activity in rats exposed to high pressure.

Free-moving rats chronically implanted in the striatum with multifiber carbon electrodes selective to dopamine were compressed in a helium-oxygen mixture to 80 bars. Extracellular dopamine level and behavioral symptoms of high-pressure neurological syndrome were simultaneously recorded. Under these conditions, the extracellular level of dopamine monitored by differential pulse voltammetry was found to be pressure dependent, and hyperlocomotor activity, a behavioral symptom of high-pressure neurological syndrome, was found to be linked to these pressure-induced changes in dopamine release.

Effect of helium-oxygen pressure on dopamine detected in vivo in the striatum of hamsters.

Free-moving hamsters chronically implanted in the striatum with carbon multifiber electrodes selective to dopamine were compressed in a helium-oxygen breathing mixture to 81 bars. Under these conditions, there was an increase in the electrochemical responses recorded from the carbon electrode by differential pulse voltammetry, which occurred during the compression and disappeared when the animals returned to the surface. This change was related to an increase in extracellular dopamine levels induced by the increase in pressure of the helium-oxygen mixture.

Effects of exponential compression curves with nitrogen injection in humans.

Two series of experiments were carried out on humans to study the effects of fast and slow exponential compression curves with N2 additions. Eight subjects in the first series and 13 subjects in the second series were analyzed up to the depths of 400-450 m of seawater (msw). The data indicated that injections of N2 in He-O2 mixture reduced or suppressed the hyperbaric tremor in the two series. Electroencephalographic (EEG) changes were recorded with the two types of compression, but these changes (increase in slow waves, decrease in alpha-activity, appearance of microsleep EEG traces) were more important with the fast exponential compression curves between 200 and 300 msw than with the slow exponential curves. The effects of the fast rates of compression on EEG activities were not compensated by addition of 4-5% N2. Consequently, the fast exponential compression curves, even with N2 injections, cannot be used without risk and must be avoided; the slow exponential compression curve with N2 injection allowed a human subject to reach 450 msw in satisfactory condition, i.e., without tremor and with light EEG changes.