Abstract: Brain insults are a major cause of acute mortality and chronic morbidity. Given the largely ineffective current therapeutic strategies, the development of new and efficient therapeutic interventions is clearly needed. A series of previous investigations has shown that the noble and anesthetic gas xenon, which has low-affinity antagonistic properties at the N-methyl-D-aspartate (NMDA) receptor, also exhibits potentially neuroprotective properties with no proven adverse side effects. Surprisingly and in contrast with most drugs that are being developed as therapeutic agents, the dose-response neuroprotective effect of xenon has been poorly studied, although this effect could be of major critical importance for its clinical development as a neuroprotectant. Here we show, using ex vivo and in vivo models of excitotoxic insults and transient brain ischemia, that xenon, administered at subanesthetic doses, offers global neuroprotection from reduction of neurotransmitter release induced by ischemia, a critical event known to be involved in excitotoxicity, to reduction of subsequent cell injury and neuronal death. Maximal neuroprotection was obtained with xenon at 50 vol%, a concentration at which xenon further exhibited significant neuroprotective effects in vivo even when administered up to 4 h after intrastriatal NMDA injection and up to at least 2 h after induction of transient brain ischemia.

Abstract: BACKGROUND AND OBJECTIVE:: Preliminary studies have shown that nitrous oxide, like xenon, may possess potentially neuroprotective properties. However, because of its possible neurotoxic and proneurotoxic effects (obtained under particular conditions) and its bad reputation at anesthetic concentrations, no thorough investigations have been performed on the potentially neuroprotective properties of nitrous oxide. The aim of this study was to investigate the possible neuroprotective effects of nitrous oxide at nonanesthetic concentrations on different models of excitotoxic insult and brain ischemia. MEASUREMENTS AND MAIN RESULTS:: Here, we show using multiple models of ex vivo and in vivo excitotoxic insults and brain ischemia that nitrous oxide, administered alone at nonanesthetic doses, offers global neuroprotection from reduction of neurotransmitter release induced by ischemia to reduction of subsequent cell injury. In vivo, in rats subjected to transient cerebral ischemia, nitrous oxide at 50 vol% offers full neuroprotection at both the histologic and neurologic outcome levels when administered up to 2 hrs, but not 3 hrs, after ischemia onset. CONCLUSIONS:: These data provide experimental evidence that nitrous oxide, which is a cost-efficient and easily available gas, has potentially neuroprotective properties in rodents when given alone at nonanesthetic concentrations. Therefore, because there is a lot at stake for the affected patients and society-in terms of easy access to treatment, profound impact of brain damage, cost of treatment, and subsequent financial cost on society-we believe that further studies should investigate thoroughly the possible potential clinical interest of nitrous oxide for the treatment of ischemic stroke in terms of optimal indications, type of ischemic injury, duration and time points for treatment, and the optimal concentration of gas to be used in clinical circumstances.

Abstract: 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.

Abstract: Though many drugs have been proven to reduce ischemia-induced brain damage in animal models, most of them have failed to reach clinical trials or, if not, have not been proven to be efficient in humans suffering stroke. Here, by performing a global analysis of recently published data in eighty nine rats subjected to middle cerebral artery occlusion (MCAO)-induced transient focal cerebral ischemia, we show that the ability of the animals to recover motor function is dependent on and highly correlated to their percentage of healthy cortex (r=0.973; P<0.001) and healthy subcortical brain structures (r=0.916; P<0.001). In addition, data analysis further reveals that neuroprotection requires preserving at least 80% and 90% of the integrity of the ipsilateral hemispheris subjected to MCAO to provide partial and full functional neurologic recovery, respectively. We suggest that this should be taken into account in preclinical pharmacological studies to estimate the actual potentially clinical interest of drugs developed for neuroprotection as well as to avoid developing further research on drugs that only provide mild to moderate histologic outcome.

Abstract: In contrast with most inhalational anesthetics, the anesthetic gases xenon (Xe) and nitrous oxide (N(2)O) act by blocking the N-methyl-d-aspartate (NMDA) receptor. Using x-ray crystallography, we examined the binding characteristics of these two gases on two soluble proteins as structural models: urate oxidase, which is a prototype of a variety of intracellular globular proteins, and annexin V, which has structural and functional characteristics that allow it to be considered as a prototype for the NMDA receptor. The structure of these proteins complexed with Xe and N(2)O were determined. One N(2)O molecule or one Xe atom binds to the same main site in both proteins. A second subsite is observed for N(2)O in each case. The gas-binding sites are always hydrophobic flexible cavities buried within the monomer. Comparison of the effects of Xe and N(2)O on urate oxidase and annexin V reveals an interesting relationship with the in vivo pharmacological effects of these gases, the ratio of the gas-binding sites' volume expansion and the ratio of the narcotic potency being similar. Given these data, we propose that alterations of cytosolic globular protein functions by general anesthetics would be responsible for the early stages of anesthesia such as amnesia and hypnosis and that additional alterations of ion-channel membrane receptor functions are required for deeper effects that progress to "surgical" anesthesia.

Abstract: The outcome of patients with traumatic brain injury (TBI) can be predicted by the extracellular potassium concentration and the change in energy homeostasis. In this study, the authors investigated the effects of high potassium concentrations on extracellular levels of glucose, pyruvate and lactate in the rat striatum. Applying artificial cerebrospinal fluid (ACSF) enriched with 120 mM potassium by reverse microdialysis leads to an increase in lactate and reduction in glucose and pyruvate. Consequently, the lactate to pyruvate ratio was also increased. These data are discussed in the context of recent studies on lactate/pyruvate conversion and the potential mechanisms whereby high potassium could affect this equilibrium. We conclude that ischemic-like events are unlikely to explain these K(+)-induced changes.

Abstract: Generalized convulsive seizures increase glucose utilization within the brain but their impact on metabolism is not well known. The striatum receives excitatory input from widespread sources in the brain and could potentially reflect energy depletion in the brain resulting from generalized seizures. We utilized multiprobe microdialysis in freely moving rats subjected to maximal electroshock to simultaneously measure glucose, lactate, and pyruvate levels in the interstitial space within striatum and in peripheral subcutaneous tissue. A brief convulsive seizure was associated with marked changes in striatal and peripheral metabolism during the post-ictal state that lasted up to 1 h. There were significant central and peripheral elevations of glucose, pyruvate, and lactate, reflecting increased glucose metabolism. Interestingly, the lactate-to-pyruvate ratio increased significantly in the periphery but remained unchanged in the striatum. Thus, there appears to be brain mechanisms that maintain adequate energy sources and prevent anaerobic shift during the post-ictal state.

Abstract: Tumoral growth effects on brain circuitry and neurochemical activities remain poorly documented. This study evaluates C6 graft effects on striatal dopaminergic afferent projections at both anatomical and functional levels. Immunohistochemistry was performed to investigate changes in neurofilament (NF), tyrosine hydroxylase (TH) and dopamine transporter (DAT) expression. Dopaminergic turnover was assessed using multiprobe microdialysis in freely-moving rat. In C6 graft striatum, dopamine (DA) catabolites were reduced in glioblastoma (DOPAC: -61%, HVA: -62%). In contrast, the DA level remained unchanged. Staining for NF, TH and DAT was drastically decreased inside the tumor. Our histological data report that striatal tumoral growth is associated with a decrease in the density of dopaminergic endings which can explain, at least in part, the decrease in DA turnover. The decrease in DAT transporter expression and the lack of change in DA level may result from an increase in DA diffusion from the peripheral areas of the tumor. In conclusion, glioblastoma growth has major consequences on the local neuronal circuitry and its neurochemistry. Changes in inter-connections and neurotransmitter turnover may result in abnormal neuronal firing activity and participate in clinical disorders associated with glioblastoma diagnosis.

Abstract: Previous studies have demonstrated opposite effects of high-pressure helium and nitrogen on extracellular dopamine (DA) levels, which may reflect disturbances on the synthesis, release or metabolic mechanisms. Intrastriatal microdialysis was used to measure the precursor (tyrosine), DA and its metabolites (DOPAC, HVA) levels under nitrogen- or helium- at pressure up to 3 MPa. Under 3 MPa of helium-oxygen breathing mixtures, the extracellular concentration of tyrosine is decreased while the extracellular concentration of DA is increased. On the contrary, nitrogen-oxygen breathing mixture at the same pressure increased extracellular tyrosine concentration and decreased DA release. Under both conditions, an increment of the DOPAC and HVA levels could be noted. Our results suggest that changes in DA release and metabolism during high-pressure helium exposure reflect the effect of the pressure per se, whereas the intrinsic effects of narcotic gases, although sensitive to pressure, would be revealed by hyperbaric nitrogen exposure.

Abstract: This report describes technical adaptations of a traumatic brain injury (TBI) model-largely inspired by Marmarou-in order to monitor microdialysis data and PtiO2 (brain tissue oxygen) before, during and after injury. We particularly focalize on our model requirements which allows us to re-create some drastic pathological characteristics experienced by severely head-injured patients: impact on a closed skull, no ventilation immediately after impact, presence of diffuse axonal injuries and secondary brain insults from systemic origin...We notably give priority to minimize anaesthesia duration in order to tend to banish any neuroprotection. Our new model will henceforth allow a better understanding of neurochemical and biochemical alterations resulting from traumatic brain injury, using microdialysis and PtiO2 techniques already monitored in our Intensive Care Unit. Studies on efficiency and therapeutic window of neuroprotective pharmacological molecules are now conceivable to ameliorate severe head-injury treatment.

Abstract: Inhaled anesthetics, including the gaseous anesthetics nitrous oxide and xenon, are thought to act by interacting directly with ion-channel receptors. In contrast, little is known about the mechanism of action of inert gases that show only narcotic potency at high pressures, such as nitrogen or argon. In the present study, we investigated the effects of selective gamma-aminobutyric acid (GABA) receptor antagonists on narcosis produced by nitrogen, argon, and nitrous oxide. Pretreatment with the competitive GABA(A) receptor antagonist gabazine (0.2 nmol) but not the GABA(B) receptor antagonist 2-hydroxysaclofen (10 nmol) increased the nitrogen and argon threshold pressure for loss-of-righting-reflex (P < 0.005) but had no effect on nitrous oxide narcosis. Pretreatment with the GABA(A) benzodiazepine receptor antagonist flumazenil (5 nmol) also increased the narcosis threshold pressure of argon (P < 0.025). Given that neither 2-hydroxysaclofen, gabazine, nor flumazenil at the doses used induced hyperexcitability, our results support a selective antagonism by gabazine and flumazenil of the narcotic action of nitrogen and argon. Some mechanisms of nitrogen and argon narcotic action might be similar to those of clinical inhaled anesthetics. IMPLICATIONS: We studied the effects in the rat of gamma-aminobutyric acid (GABA) receptor antagonists on narcosis induced by nitrogen and argon that act only at high pressures. Our results show that the GABA (A) receptor may play a significant role, suggesting that some mechanisms might be similar to those of clinical inhaled anesthetics.

Abstract: Inert gas narcosis is a neurological syndrome appearing when humans or animals are exposed to hyperbaric inert gases (nitrogen, argon) composed by motor and cognitive impairments. Inert gas narcosis induces a decrease of the dopamine release at the striatum level, structure involved in the regulation of the extrapyramidal motricity. We have investigated, in freely moving rats exposed to different narcotic conditions, the relationship between the locomotor and motor activity and the striatal dopamine release, using respectively a computerized device that enables a quantitative analysis of this behavioural disturbance and voltammetry. The use of 3 MPa of nitrogen, 2 MPa of argon and 0.1 MPa of nitrous oxide, revealed after a transient phase of hyperactivity, a lower level of the locomotor and motor activity, in relation with the decrease of the striatal dopamine release. It is concluded that the striatal dopamine decrease could be related to the decrease of the locomotor and motor hyperactivity, but that other(s) neurotransmitter(s) could be primarily involved in the behavioural motor disturbances induced by narcotics. This biphasic effect could be of major importance for future pharmacological investigations, and motor categorization, on the basic mechanisms of inert gas at pressure.

Abstract: The aim of this work was to study the role of pallidal GABAa and GABAb neurotransmission in the behavioral disorders induced by pressure. The effects of GABAb antagonist 5-aminovalleric acid (5-AVA) or GABAa antagonist gabazine administrations in the globus pallidus (GP) on locomotor and motor hyperactivity (LMA) and myoclonia expressions in the model of the rat submitted to 8 MPa of helium-oxygen breathing mixture were analyzed. The administration of GABAa antagonist gabazine enhances the occurrence of the epileptic seizures, slightly increases LMA but decreases myoclonia. In contrast, the administration of GABAb antagonist 5-AVA decreases both LMA and myoclonia during the compression and the beginning of the holding time at 8 MPa. These data indicate that some behavioral disorders induced by pressure are in relation with GABAergic neurotransmission and establish clearly that GABAa and GABAb receptor mediations have distinct functions in the GP of the rat.

Abstract: Reduction of central energy metabolism is a strategy to protect brain against neurotoxic events. The aim of this microdialysis study in rats is to evaluate changes in energy metabolite levels at central level (striatum) comparatively to peripheral level (subcutaneous adipose tissue) during hypothermic barbituric deep-anaesthesia (sodium pentobarbital 60 mg/kg intraperitoneally). At brain level, extracellular glucose increases (+14.9%) while lactate decreases (-16.6%); opposite results were observed at subcutaneous level (-29.2% for glucose and +68.3% for lactate). Lactate/pyruvate ratio remains unchanged at brain level, but increases at subcutaneous level (+73.5%). In light of previous studies on the effects of pentobarbital on regional blood flow and tissue glucose consumption, our data correlates the fact that pentobarbital reduces preferentially brain energetic metabolism. We suggest that those regional effects are explained, at least for a part, by the fact that central isoform glucose transporters (Glut1 and Glut3) are known to be more sensitive to pentobarbital than peripheral isoforms. Such facts can be involved in the protection of brain tissue against ischemic risk due to decreased cerebral blood flow decrease.

Abstract: In rat, helium pressures induce locomotor and motor activity which requires dopaminergic and N-methyl-D-aspartate (NMDA) receptor activities at striatal level. However, biochemical studies have suggested that pressure exposure may increase striatal glutamate level. We used microdialysis technique to study the effects of pressure on glutamate level in the striatum and the effects of local administration of D1 (SCH23390) or D2 (sulpiride) on these changes. Pressures increase both glutamate and glutamine levels in striatal microdialysates. Administration of sulpiride (1 microM) or SCH23390 (1 microM) by reverse microdialysis did not affect significantly pressure induced glutamate increase. So, protective effects of D1 and D2 antagonists against locomotor and motor hyperactivity (LMA) are probably independent of the processes involved in the striatal glutamate increase evoked by pressure.

Abstract: In mammals high pressure of helium-oxygen (He-O2) breathing mixture leads to the high pressure neurological syndrome (HPNS) which includes a set of behavioural disorders such as locomotor and motor hyperactivity (LMA) and myoclonia. In rats, i.c.v. administrations of competitive NMDA antagonists decrease some of these symptoms suggesting that He-O2 pressure could enhance NMDA neurotransmission within the central nervous system. More recently, we have shown using microdialysis that the extracellular glutamate level is increased in the striatum by He-O2 pressure. Neurochemical data have suggested that this structure is probably involved in the LMA development but not in the myoclonia expression. When considering myoclonia, recent neuropathological studies performed at normal pressure in humans suggest that the globus pallidus extern (equivalent to the globus pallidus in the rat) could be involved in this behavioural disorder. The aim of this study was to compare the role of striatal and pallidal NMDA activity on the LMA development and the myoclonia expression in the model of rat exposed to 8 MPa of He-O2 mixture. The intrastriatal administration of D(-)-2-amino-7-phosphonoheptanoic acid (2-APH) (10 nmol/slide) reduced the LMA development but only slightly reduced myoclonia. In contrast, the intrapallidal administration of 2-APH (10 nmol/slide) reduced both LMA and myoclonia. These results suggest that the LMA development requires NMDA activity at both striatal and pallidal level. In contrast, the myoclonia expression mainly requires NMDA activity at pallidal level. Consequently, NMDA neurotransmission at input and output levels of the striato-pallidal pathway play different roles in some of the behavioural disorders induced by He-O2 pressure.

Abstract: The purpose of this study is to investigate the in vivo tumoral brain metabolism in free moving rats using microdialysis. Cells from C6 glioma cell line were inoculated in one striatum 15 days before the microdialysis experimentation. Then, using a new system allowing perfusion of several microdialysis probes in free moving rat, normalised dialysate levels of glucose, lactate and pyruvate were monitored in both glioma and control striatum. At the end of the procedure, animals were sacrificed for histological study. Data shows that probe functioning is similar in both tissues. The results for normalised glucose level were in striatum control: 2.14 mM, in tumoral striatum: 1.71 mM (P>0.1); for lactate, respectively, 0.86 and 1.65 mM (P<0.05) and for pyruvate, respectively, 65.56 and 140. 94 microM (P<0.05). This data clearly shows a significant increase of pyruvate and lactate in tumoral striatum compared to normal striatum, correlating previous in vitro studies on glioma metabolism. We conclude that this microdialysis technique is of value in tumoral brain and could constitute an interesting tool for a better understanding of glioma metabolism.

Abstract: High pressure induced locomotor and motor hyperactivities (LMA), tremor and myoclonia in rat. The LMA has been reported to be reduced by intracerebroventricular (i.c.v.) administration of dopaminergic receptor antagonists. Moreover, the LMA but not myoclonia correlate with pressure induced striatal dopamine increase. Nevertheless the role of dopaminergic and NMDA receptor activities at striatal level in the development of LMA remained unclear. In this study, the microdialysis technique associated to a behavioural device was used to test the effects of intra-striatal administration of D1 antagonist SCH23390 (1 microM), D2 antagonist sulpiride (1 microM) and NMDA antagonist AP-5 (10 microM) on LMA, tremor and myoclonia expression. Data clearly showed that LMA was drastically reduced by each treatment. In contrast, tremor and myoclonia were poorly affected. These data suggest that both dopaminergic and NMDA receptor activities at striatal level are needed for the full expression of the pressure-induced LMA and confirm that striatal neurotransmission changes are principally involved in this behavioural disorders. At the light of recent studies on dopaminergic neurotransmission and glutamate evoked-NMDA activity, we suggest that blockage of D1 or D2 receptors should reduced the LMA by reducing glutamate-evoked activity.

Abstract: Narcosis is a neurological syndrome that reduces capacities of divers. Although this phenomenon appeared at the end of 19th century, the mechanisms are not yet elucidated. The greatest technical problem is that these studies are carried out under hyperbaric conditions. Nitrous oxide is known to be an inducer of narcosis, at atmospheric pressure. The aim of this study is to compare two narcotic environments; a normobaric narcosis under several percentages of nitrous oxide, and an hyperbaric narcosis under 0.9 MPa of Nitrox (N2O2 mixture). This comparison is realized on rats submitted to a fixed-ratio 15 test, in which they have to press a lever to get rewarded. The results show significant performances decreases: the number of pressed lever are reduced by 50% under Nitrox and by 70% under N2O. Nitrous oxide could be considered as a normobaric model of hyperbaric narcosis.

Abstract: Inert gas narcosis is a neurological syndrome inducing several psychomotor disorders. Nitrogen narcosis represents the major cause of performances decrease concerning divers, in the depth range of 30 to 90 meters (0.3 to 0.9 MegaPascal). As narcosis affects motor functions, we chose to study the nigro-striatal dopaminergic pathway owing to its involvement in psychomotor disorders. The aim of this study is to compare, in the Sprague-Dawley rats striatium, changes in extracellular concentrations of Dopamine and its metabolites: Dihydroxyphenylacetic Acid (DOPAC) and Homovanillic Acid (HVA) under a normobaric narcosis (20; 40, and 60% of Nitrous Oxide (N2O)) on one hand, and under 0.9 MegaPascal of Nitrox (Nitrogen Oxygen normoxic mixture) on the other hand. In fact, if these two conditions are similar, normobaric narcosis would allow us to explain nitrogen narcosis mechanisms without any pressure effect. The first emergence of Dopamine and metabolites variations occurs around 40% of N2O. Dopamine decreases by 45% and is accompanied by a DOPAC diminution of 7% while HVA concentrations remain constant. Under 60% N2O, these decrease have a greater amplitude. The Dopamine variations obtained under 0.9 Mpa of Nitrox are closed to alterations induced by 60% of N2O (DA decreases by 70%).

Abstract: In this work, we report a new analysis system to quantify the behavioral disorders observed in the model of the rat submitted to high pressure and monitored by piezoelectric sensor. The major advance consists in a spectral 3D representation of LMA and tremor, which provides a better selectivity than previous systems. This behavioral processing indicated that tremor is characterized by a 7-14 Hz frequency band and LMA by a 20-35 Hz frequency band. The association of this system to the microdialysis technique to simultaneously evaluate the striatal DA level confirms that pressure-induced striatal DA increase is in great part linked to the LMA, and supports the concept of a complex ethiology for this symptom. We conclude that this new behavioral system analysis associated with microdialysis study constitutes a powerful tool to investigate the role of different neurotransmitters in the occurrence of the behavioral components described in the HPNS of rats.

Abstract: High pressure is known as a basic etiological factor underlying central nervous system changes known as the high pressure neurological syndrome (HPNS). In the rat, HPNS includes behavioural disturbances including locomotor and motor hyperactivities (LMA) linked to a striatal dopamine (DA) increase. Recent findings have shown that intracerebroventricular administration of 5-HT3 or 5-HT1b antagonists decrease both LMA and striatal DA increase suggesting that pressure could enhance the serotonin (5-HT) neurotransmission. In this study, for the first time, the striatal levels of DA and 5-HT were simultaneously monitored using microdialysis in free-moving rats exposed to high pressure. Our results show that the striatal 5-HT level increases during pressure exposure. These data suggest that pressure-induced striatal 5-HT increase could participate in the increasing DA release. Nevertheless, the lack of correlation between striatal DA and 5-HT changes suggests that other processes are involved in the pressure-induced striatal DA increase.

Abstract: In man, nitrogen narcosis is characterized by euphoria, impaired cognitive function, neuromuscular incoordination and, ultimately, loss of consciousness. Because of the motor movement disorders, we chose to study the nigrostriatal system, whose major function is to regulate the extrapyramidal nervous system. The purpose of this investigation was to monitor changes in extracellular levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum of conscious rats, using intracerebral microdialysis. Results show a 40% decrease in extracellular DA concentration, a 59% increase in extracellular DOPAC and an increase in HVA starting with exposure to the nitrogen mixture. Thirty minutes after the beginning of the exposure, a compensation phase took place. HVA returns to its initial basal value, and levels of DOPAC and DA returned towards normal but never reached their initial values. These results contrast with those observed during the High Pressure Neurological Syndrome (HPNS, 5.1 MPa of helium pressure) in which there is a significant increase in extracellular DA. Therefore, some of the symptoms of nitrogen narcosis may be linked with the decrease in the extracellular DA levels.

Abstract: When human divers and experimental animals are exposed to high pressure of helium-oxygen mixture, they develop the high pressure neurological syndrome, characterized by nausea, vertigo, tremor, myoclonus, EEG modifications and convulsions. Free-moving rats were stereotaxically implanted in the anterior caudate nucleus with a microdialysis probe to measure dopamine, dihydroxyphenylacetic acid and homovanillic acid levels during different phases of a simulated dive up to 5.1 MPa. Compression was found to cause an increase in extracellular dopamine and dihydroxyphenylacetic acid concentrations, but not in homovanillic acid. This represents a specific effect of high pressure on the dopaminergic pathway. Recent findings on D2 autoreceptors, showing a decrease in receptor affinity under pressure, allow us to conclude that pressure increases dopamine synthesis through a direct action on D2 autoreceptors.

Abstract: Using an electrical stimulation of the reticulospinal tract at the level of the medial longitudinal fasciculus, the effects, and the neurochemical mechanisms of these effects, of a progressive increase in helium-oxygen pressures, up to 50 bar, on the spinal cord excitability in the chronic rat are investigated. In control animals, high pressure exposure over 30 bar was found to increase markedly the electromyogram response evoked in nuchal muscles. This startlelike response was monosynaptically induced by stimulation of the reticulospinal tract. Conversly, no hyperbaric alteration in spinal excitability has been observed in animals pretreated with the classical 5-HT antagonist drug metergoline. These results emphasize the importance of spinal cord as a potential target for mediating hyperbaric effects on sensorimotor behaviors (i.e., motor disturbances of the HPNS). Moreover, our work suggests that serotonin could be implicated in hyperbaric spinal cord hyperexcitability.

Abstract: In three experiments, startle responses to brief intense tone-bursts (30 msec, 110 dB, 6000 Hz) and single pulse (0.1 msec) stimulation of the cochlear nucleus and the nucleus reticularis pontis caudalis are studied under high pressures of heliox (from 0 bar to 50 bars) in the rat. For each rat (N = 12), mean amplitude and latency changes in startle responses (nuchal electromyography and whole-body accelerometry) are compared at normobaric pressure and during compression, at a speed of 100 bar/H. The results indicate that high pressures decrease (50% of control size) tone evoked startle by acting on the peripheral auditory organ, probably through middle and/or inner ear barotrauma. The large increases in electrically-elicited startle (250% of control size) from the cochlear and reticular nuclei, under hyperbaric conditions, suggest that high pressures affect sensorimotor reactivity by excitatory action on synaptic transmission in the relays of the acoustic startle reflex arc at the lower brainstem and spinal levels. Startle latencies remain unaffected by the heliox high pressures studied here.