Alteration of striatal dopamine levels under various partial pressure of oxygen in pre-convulsive and convulsive phases in freely-moving rats.

The purpose of this study was to investigate the change in the striatal dopamine (DA) level in freely-moving rat exposed to different partial pressure of oxygen (from 1 to 5 ATA). Some works have suggested that DA release by the substantia nigra pars compacta (SNc) neurons in the striatum could be disturbed by hyperbaric oxygen (HBO) exposure, altering therefore the basal ganglia activity. Such changes could result in a change in glutamatergic and GABAergic control of the dopaminergic neurons into the SNc. Such alterations could provide more information about the oxygen-induced seizures observed at 5 ATA in rat. DA-sensitive electrodes were implanted into the striatum under general anesthesia. After 1 week rest, awaked rats were exposed to oxygen-nitrogen mixture at a partial pressure of oxygen of 1, 2, 3, 4 and 5 ATA. DA level was monitored continuously (every 3 min) by in vivo voltammetry before and during HBO exposure. HBO induced a decrease in DA level in relationship to the increase in partial pressure of oxygen from 1 ATA to 4 ATA (-15 % at 1 ATA, -30 % at 2 ATA, -40 % at 3 ATA, -45 % at 4 ATA), without signs of oxygen toxicity. At 5 ATA, DA level strongly decreases (-75 %) before seizure which occurred after 27 min ± 7 HBO exposure. After the epileptic seizure the decrease in DA level disappeared. These changes and the biphasic effect of HBO were discussed in function of HBO action on neurochemical regulations of the nigro striatal pathway.

Mechanism of action of nitrogen pressure in controlling striatal dopamine level of freely moving rats is changed by recurrent exposures to nitrogen narcosis.

In rats, a single exposure to 3 MPa nitrogen induces change in motor processes, a sedative action and a decrease in dopamine release in the striatum. These changes due to a narcotic effect of nitrogen have been attributed to a decrease in glutamatergic control and the facilitation of GABAergic neurotransmission involving NMDA and GABA(A) receptors, respectively. After repeated exposure to nitrogen narcosis, a second exposure to 3 MPa increased dopamine levels suggesting a change in the control of the dopaminergic pathway. We investigated the role of the nigral NMDA and GABA(A) receptors in changes in the striatal dopamine levels. Dopamine-sensitive electrodes were implanted into the striatum under general anesthesia, together with a guide-cannula for drug injections into the SNc. Dopamine level was monitored by in vivo voltammetry. The effects of NMDA/GABA(A) receptor agonists (NMDA/muscimol) and antagonists (AP7/gabazine) on dopamine levels were investigated. Rats were exposed to 3 MPa nitrogen before and after five daily exposures to 1 MPa. After these exposures to nitrogen narcosis, gabazine, NMDA and AP7 had no effect on the nitrogen-induced increase in dopamine levels. By contrast, muscimol strongly enhanced the increase in dopamine level induced by nitrogen. Our findings suggest that repeated nitrogen exposure disrupted NMDA receptor function and decreased GABAergic input by modifying GABA(A) receptor sensitivity. These findings demonstrated a change in the mechanism of action of nitrogen at pressure.

Effect of long-term administration of the antidepressant drug milnacipran on serotonergic and noradrenergic neurotransmission in the rat hippocampus.

The effect of a long-term administration of the antidepressant milnacipran on the function of the serotonergic (5-HT) and noradrenergic (NE) systems was studied using single cell recording of CA3 hippocampal pyramidal cells in chloral hydrate-anesthetized male Sprague-Dawley rats, and in vitro [3H]5-HT release measurement from hippocampal slices. The sensitivity of neither the extrasynaptic nor that of the postsynaptic 5-HT1A receptors of the pyramidal neurons was altered, as indicated by their unchanged responsiveness to the microiontophoretic application of 5-HT, and by the unchanged effect of the electrical stimulation at low frequency of the ascending 5-HT bundle, respectively. Increasing the frequency of stimulation (from 1 to 5 Hz) decreased its efficacy in control rats; the milnacipran treatment abolished this phenomenon. This cannot be attributed to a desensitisation of the terminal 5-HT1B autoreceptor, since the suppressive effect of 5-HT agonist 5-carboxyamidotryptamine on [3H]5-HT release was enhanced in milnacipran-treated rats. As for the NE system, the unchanged suppressing effect of microiontophoretic applications of NE and that of the 5 Hz stimulation in the locus coeruleus (LC) on the firing activity of pyramidal neurons indicates that the milnacipran treatment not altered the sensitivity of extrasynaptic alpha2- and postsynaptic alpha1-adrenergic receptors on pyramidal cells, as well as that of the presynaptic alpha2-autoreceptor on NE terminals. The decreased inhibitory effect of NE on the [3H]5-HT release in milnacipran-treated rats revealed that this treatment results in a desensitisation of the presynaptic alpha2-heteroreceptor located on serotonergic terminals. Taken together with the decreased suppressive effect of a low frequency of stimulation of the NE tract, the present results suggest that long-term milnacipran treatment enhances the efficacy of the 5-HT and reduces that of the NE neurotransmission.

Could hyperoxic ventilation impair oxygen delivery in septic patients?

OBJECTIVE: In critically ill patients, a decrease in whole body oxygen consumption under hyperoxia has been reported and this could be related to hyperoxia-induced arterial changes. We investigated changes in brachial artery circulation and tone during short-term hyperoxic ventilation in septic patients. DESIGN AND SETTING: Prospective clinical study in the intensive care unit of a university hospital. PATIENTS: Fourteen patients (severe sepsis n=3 and septic shock n=11) requiring mechanically controlled ventilation due to sepsis syndrome were investigated under stable clinical conditions. INTERVENTIONS: After a 20-min period of hyperoxic ventilation (inspired oxygen fraction = 100%), two-dimensional images of brachial artery cross-sectional area and brachial blood flow velocities were recorded using conventional ultrasonography and pulsed Doppler simultaneously with invasive arterial pressure measurements. MEASUREMENTS AND MAIN RESULTS: Hyperoxia did not affect heart rate, but increased mean arterial pressure and decreased cross-sectional areas both at the end of diastole and at the end of systole. Haemodynamic study showed an increase in resistance index, and a decrease in distensibility and compliance coefficients. Furthermore, a decrease in brachial artery blood flow and arterial oxygen delivery was observed during hyperoxic exposure. CONCLUSIONS: Hyperoxia was paradoxically demonstrated to decrease oxygen delivery in upper limbs during septic shock.

Effects of repeated hyperbaric nitrogen-oxygen exposures on the striatal dopamine release and on motor disturbances in rats.

Previous studies have demonstrated disruptions of motor activities and a decrease of extracellular dopamine level in the striatum of rats exposed to high pressure of nitrogen. Men exposed to nitrogen pressure develop also motor and cognitive disturbances related to inert gas narcosis. After repetitive exposures, adaptation to narcosis was subjectively reported. To study the effects of repetitive exposures to hyperbaric nitrogen-oxygen, male Sprague-Dawley rats were implanted in the striatum with multifiber carbon dopamine-sensitive electrodes. After recovery from surgery, free-moving rats were exposed for 2 h up to 3 MPa of nitrogen-oxygen mixture before and after one daily exposure to 1 MPa of nitrogen-oxygen, for 5 consecutive days. Dopamine release was measured by differential pulse voltammetry and motor activities were quantified using piezo-electric captor. At the first exposure to 3 MPa, the striatal dopamine level decreased during the compression (-15%) to reach -20% during the stay at 3 MPa. Motor activities were increased during compression (+15%) and the first 60 min at constant pressure (+10%). In contrast, at the second exposure to 3 MPa, an increase of dopamine of +15% was obtained during the whole exposure. However, total motor activities remained unchanged as compared to the first exposure. Our results confirm that nitrogen exposure at 3 MPa led to a decreased striatal dopamine release and increased motor disturbances in naïve rats. Repetitive exposures to 1 MPa of nitrogen induced a reversal effect on the dopamine release which suggests a neurochemical change at the level of the neurotransmitter regulation processes of the basal ganglia. In contrast, motor activity remained quantitatively unchanged, thus suggesting that dopamine is not involved alone in modulating these motor disturbances.

Opposing effects of narcotic gases and pressure on the striatal dopamine release in rats.

Nitrogen-oxygen breathing mixtures, for pressures higher than 0.5 MPa, decrease the release of dopamine in the rat striatum, due to the narcotic potency of nitrogen. In contrast, high pressures of helium-oxygen breathing mixtures of more than 1-2 MPa induce an increase of the striatal dopamine release and an enhancement of motor activity, referred to as the high pressure nervous syndrome (HPNS), and attributed to the effect of pressure per se. It has been demonstrated that the effect of pressure could be antagonized by narcotic gas in a ternary mixture, but most of the narcotic gas studies measuring DA release were executed below the threshold for pressure effect. To examine the effect of narcotic gases at pressure on the rat striatal dopamine release, we have used two gases, with different narcotic potency, at sublethargic pressure, nitrogen at 3 MPa and argon at 2 MPa. In addition, to dissociate the effect of the pressure, we have used nitrous oxide at 0.1 MPa to induce narcosis at very low pressure, and helium at 8 MPa to study the effect of pressure per se. In all the narcotic conditions we have recorded a decrease of the striatal dopamine release. In contrast, helium pressure induced an increase of DA release. For the pressures used, the results suggest that the decrease of dopamine release was independent of such an effect of the pressure. However, for the same narcotic gas, the measurements of the extracellular DA performed in the striatum seem to reflect an opposing effect of pressure, since the decrease in DA release is lower with increasing pressure.

GABAergic modulation in the substantia nigra of the striatal dopamine release and of the locomotor activity in rats exposed to helium pressure.

Helium-oxygen pressure induces in rodents an increase of both locomotor and motor activity (LMA) and of the striatal dopamine release, which could result from a decrease of GABA transmission in the substantia nigra. The effects of the GABA(A) receptor agonist muscimol and of the GABA(B) receptor agonist baclofen on the striatal dopamine release were measured using differential pulse voltammetry. Behavioural studies were performed in freely moving rats using actimetry. Whatever the drug used under helium pressure, bilateral administration in the substantia nigra pars reticulata (SNr) or in the substantia nigra pars compacta (SNc) counteracted the evoked dopamine release. However, only the baclofen reduced the LMA, while the muscimol administration in the SNr, but not in the SNc, increased it. These results indicate that different subtypes of GABA receptors would be involved in the control of the DA release and in the occurrence of LMA under helium pressure.

Microdialysis study of striatal dopaminergic dysfunctions induced by 3 MPa of nitrogen- and helium-oxygen breathing mixtures in freely moving rats.

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.

Nitrous oxide reverses the increase in striatal dopamine release produced by N-methyl-D-aspartate infusion in the substantia nigra pars compacta in rats.

Bilateral administration of NMDA (5 x 10(-10) mol) in the substantia nigra pars compacta increases the striatal dopamine (DA) release. However, this enhancing effect of NMDA was suppressed by nitrous oxide exposure at 0.1 MPa, which induced per se a decrease of the DA release. These results show that nitrous oxide exerts a reversal effect on the increase in striatal DA release produced by NMDA receptor activation in the substantia nigra pars compacta. This observation may be related to the fact that nitrous oxide is thought to produce its effects by acting as an NMDA receptor antagonist.

Indirect presynaptic modulation of striatal dopamine release by GABA(B) receptors in the rat substantia nigra.

Regulation of striatal dopamine release by gamma-aminobutyric acid (GABA) neurotransmission was investigated using voltammetry in freely moving rats, following focal injection of the GABA(B) receptor agonist baclofen or the GABA(B) receptor antagonist 5-aminovaleric acid (5-AVA) in either the substantia nigra pars reticulata (SNr) or the substantia nigra pars compacta (SNc). Administration in the SNr of baclofen and 5-AVA at the dose of 2 pg, but not of 0.2 pg, resulted in a decrease and an increase in striatal dopamine release, respectively. In contrast, when injected in the SNc, 5-AVA only produced a transient increase in striatal dopamine release, while baclofen remained ineffective. This suggests that GABA(B) receptors in the SNr, but not the SNc, may play a major role in the control of nigrostriatal dopamine (DA) activity and the release of DA in the striatum.

Striatal dopamine release and biphasic pattern of locomotor and motor activity under gas narcosis.

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.

Alterations in nigral NMDA and GABAA receptor control of the striatal dopamine level after repetitive exposures to nitrogen narcosis.

Nitrogen pressure exposure in rats results in decreased dopamine (DA) release at the striatal terminals of the substantia nigra pars compacta (SNc) dopaminergic neurons, demonstrating the narcotic potency of nitrogen. This effect is attributed to decreased excitatory and increased inhibitory inputs to dopaminergic neurons, involving a change in NMDA and GABA(A) receptor function. We investigated whether repetitive exposures to nitrogen modify the excitatory and inhibitory control of the dopaminergic nigro-striatal pathway. We used voltammetry to measure dopamine levels in freely-moving rats, implanted with dopamine-sensitive electrodes in the striatum. NMDA/GABA(A) receptor agonists (NMDA/muscimol) and antagonists (AP7/gabazine) were administered through a guide-cannula into the SNc, and their effects on striatal dopamine levels were measured under normobaric conditions, before and after five repetitive exposures to 1 MPa nitrogen. NMDA-mediated dopamine release was greater following repetitive exposures, AP7-mediated inhibition of glutamatergic input was blocked, suggesting that NMDA receptor sensitivity was increased and glutamate release reduced. Muscimol did not modify dopamine levels following repetitive exposures, whereas the effect of gabazine was greater after exposures than before. This suggested that interneuronal GABA(A) receptors were desensitized, leading to an increased GABAergic input at dopaminergic cells. Thus, repetitive nitrogen exposure induced persistent changes in glutamatergic and GABAergic control of dopaminergic neurons, resulting in decreased activity of the nigrostriatal pathway.

The role of NMDA and GABAA receptors in the inhibiting effect of 3 MPa nitrogen on striatal dopamine level.

Nitrogen pressure exposure, in rats, resulted in a decreased dopamine (DA) level by the striatal terminals of the substantia nigra pars compacta (SNc) dopaminergic neurons, due to the narcotic potency of nitrogen. In the SNc, the nigrostriatal pathway is under glutamatergic and GABAergic control mediated by ion-channel NMDA and GABA(A) receptors, main targets of volatile anesthetics. The aim of this study was to investigate the role of these receptors in the regulation of striatal dopamine level under nitrogen narcosis. Under general anesthesia, male Sprague-Dawley rats were bilaterally implanted in the striatum with dopamine-sensitive electrodes and, in the SNc, with guide cannulae for drug injections. After recovery from surgery, the striatal dopamine level was quantified using differential pulse voltammetric measurements in freely moving rats. Focal injections of agonists (NMDA/muscimol) and antagonists (AP7/gabazine) of NMDA/GABA(A) receptors were made within SNc. Both normobaric condition and 3 MPa nitrogen pressure were studied. Control experiments confirmed a direct glutamatergic control on the striatal DA level through NMDA receptors. Both direct and indirect GABAergic control through two different types of GABA(A) receptors located on GABAergic interneurons and on DA cells were indicated. Under nitrogen pressure, the decrease in dopamine level (20%) was suppressed by both NMDA and GABA(A) agonist infusion. There was an unexpected increasing DA level, induced by AP7 (about 10%) and gabazine (about 30%). These results indicate that NMDA receptors remain functional and suggest a decreased glutamate release. The findings also describe an increase of GABA(A) receptor-mediated inhibition on DA cells under nitrogen pressure exposure.

Effect of flumazenil on GABAA receptors in isolated rat hippocampal neurons.

Using whole cell patch-clamp recordings from pyramidal cells acutely dissociated from rat hippocampal slices, Ro-15 1788 (flumazenil, FLU) was shown to enhance the GABAA-receptor mediated currents evoked by application of gamma-aminobutyric acid (GABA) and to antagonize the enhancing effect of the benzodiazepine agonist flurazepam (FZP) on the GABAA response. Both FLU and FZP increased the peak and the steady-state components of the responses and accelerated the current decay. This suggests that both agents act via a common mechanism on GABA transmission. It is concluded that FLU possesses high affinity for the binding site, but low efficacy on the GABAA-benzodiazepine receptor. This suggests that FLU acts as a partial agonist on GABAA receptors.

GABA(A) receptors in the pars compacta and GABA(B) receptors in the pars reticulata of rat substantia nigra modulate the striatal dopamine release.

The nigral GABAergic regulation of striatal dopamine release was investigated using voltammetry in freely moving rats. The local administration of muscimol (1 nM) in the substantia nigra pars compacta, but not in the substantia nigra pars reticulata, increased the striatal dopamine release. In contrast, the administration of baclofen (10 nM) in the substantia nigra pars reticulata, but not in the substantia nigra pars compacta, produced a decrease of the striatal dopamine release. Opposite effects were respectively observed after administration of GABA(A) and GABA(B) antagonists. These data lead us to suggest a differential presynaptic GABAergic control of the dopaminergic neurotransmission through GABA(A) receptors in the substantia nigra pars compacta, and GABA(B) receptors in the substantia nigra pars reticulata.