Cognitive performance during a simulated climb of Mount Everest: implications for brain function and central adaptive processes under chronic hypoxic stress.

High altitude is characterized by hypoxic environmental conditions and is well known to induce both physiological and psychological disturbances. In the present study, called "Everest-Comex 97", the authors investigated the effects of high altitude on the psychosensorimotor and reasoning processes of eight climbers participating in a simulated climb from sea level to 8,848 m over a 31-day period of confinement in a decompression chamber. Tests of visual reaction time, psychomotor ability, and number ordination were used. The climbers' data were compared with data from a similar laboratory study at sea level in control subjects. Continued testing of the control subjects at sea level clearly led to learning effects and improvement of performance in psychomotor ability and number ordination. In the climbers, similar learning effects occurred up to an altitude of 5,500­6,500 m. With further increases in altitude, the climbers' psychomotor performance and mental efficiency deteriorated progressively, leading to significant differences in psychomotor ability and mental efficiency between control subjects and climbers (9 and 13% respectively at 8,000 m and 17.5 and 16.5% respectively at 8,848 m). Three days (72 h) after the climbers had returned to sea level, their mental and psychomotor performances were still significantly lower than those of control subjects (by approximately 10%). In contrast, visual reaction time showed no significant changes in either climbers or control subjects. It is suggested that chronic hypoxic stress could alter selectively mental learning processes, i.e. explicit, rather than implicit (stimulus-response learning processes) memory and cortico-limbic rather than basal ganglia-sensorimotor system function.

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.

Administration of the glutamate uptake inhibitor L-trans-PDC in the globus pallidus and the substantia nigra, but not in the striatum, attenuates the psychostimulant effect of high helium pressure on locomotor activity in the rat.

High helium pressure of more than 2 MPa produces central neuroexcitatory motor behavior. In rodents, symptoms comprise locomotor and motor activity (LMA), myoclonia, and, at pressure greater than 9-10 MPa, convulsions and tonic-clonic seizures. We studied the behavioral effects of bilateral injection of the glutamate uptake inhibitor L-trans-pyrollidine-2,4-dicarboxylic acid (L-trans-PDC), in either the substantia nigra reticulata (SNr), the globus pallidus (GP), or the striatum on high helium pressure-induced LMA and myoclonia. Injection of L-trans-PDC in the GP and the SNr attenuated LMA, whereas injection in the striatum enhanced it. Alternatively, injection of L-trans-PDC in the SNr increased myoclonia, whereas injection in the GP or the striatum showed no effects on myoclonia. These results confirm that helium pressure-induced LMA and myoclonia have different neural origins. According to current thinking on basal ganglia function and previous data, it is suggested that high helium pressure would lead to a reduction of glutamate transmission in the SNr that could contribute to a reduction in activity of the nigrothalamic GABA pathway and then to the occurrence of LMA. It is further suggested that glutamate and DA transmissions in the striatum could have synergistic, rather than antagonistic, influences on motor activity.

Sigmoidal compression rate-dependence of inert gas narcotic potency in rats: implication for lipid vs. protein theories of inert gas action in the central nervous system.

Inert gases at raised pressure exert anaesthetic effects. It is assumed that anaesthesia by the inert gases is fundamentally similar to anaesthesia produced by general anaesthetics. However, do general anaesthetics bind directly to proteins or influence activity by indirectly perturbing membrane lipids still remains a major question. Although the pressure required to achieve anaesthesia with inert gases has been suggested to exert potentially some pressure antagonism per se, this has not been studied yet to our knowledge. We investigated this possibility using nitrogen, argon, and nitrous oxide. Whatever the narcotic agent used, our results showed that the pressure of narcotic required to induce anaesthetic effects increased, as compression rate increased, in a sigmoid fashion rather than in a linear fashion. Evidence for sigmoïdal responses vs. linear responses depended of the narcotic potency of the anaesthetic agent used (nitrogen: r2=0.973 vs. r2=0.941; argon: r2=0. 971 vs. r2=0.866; nitrous oxide: r2=0.995 vs. r2=0.879). Since a linear antagonism is predicted by lipid theories, we think it likely that these findings indicate that inert gases bind to a modulatory site of a protein receptor and act as allosteric modulators. Since other workers provided evidence for binding processes using volatile anaesthetics, the present findings could indicate that all classes of general anaesthetics, including inert gases, could act by binding directly to proteins rather than by dissolving in some lipids of the cellular membrane.

Crucial role of the 5-HT2C receptor, but not of the 5-HT2A receptor, in the down regulation of stimulated dopamine release produced by pressure exposure in freely moving rats.

Helium pressure of more than 2 MPa is a well known factor underlying pressure-dependent central neuroexcitatory disorders, referred to as the high-pressure neurological syndrome. This includes an increase in both serotonin (5-HT) and dopamine (DA) release. The relationship between the increase in 5-HT transmission produced by helium pressure and its effect on DA release has been clarified in a recent study, which have first demonstrated that the helium pressure-induced increase in DA release was dependent on some 5-HT receptor activation. In the present study, we examined in freely moving rats the role of 5-HT2A and 5-HT2C receptors in the increase in DA release induced by 8 MPa helium pressure. We used the 5-HT2A receptor antagonist ketanserin and the 5-HT2C receptor agonist m-CPP which have been demonstrated to reduce DA function. Because neither ketanserin is an ideal 5-HT2A receptor antagonist nor m-CPP an ideal 5-HT2C receptor agonist, additional experiments were made at normal pressure to check up on the selectivity of ketanserin and m-CPP for 5-HT2A and 5-HT2C receptors, respectively. Administration of m-CPP reduced both DA basal level and the helium pressure-induced increase in DA release, whereas administration of ketanserin only showed a little effect on the increase in DA release produced by high helium pressure. These results suggest that the 5-HT2C receptor, but not the 5-HT2A receptor, would play a crucial role in the helium pressure-induced increase in DA release. This further suggests that helium pressure may simultaneously induce an increase in 5-HT transmission at the level of 5-HT2A receptors and a decrease in 5-HT transmission at the level of 5-HT2C receptors.

Involvement of 5-HT3 receptor in the pressure-induced increase in striatal and accumbens dopamine release and the occurrence of behavioral disorders in free-moving rats.

Rats exposed to high pressure developed locomotor and motor activity (LMA) that correlated with an increase of DA release in both the nucleus accumbens and the caudate-putamen. We investigated the effects of the 5-HT3 receptor antagonist MDL 72222 on these pressure-induced neurochemical and behavioral disorders. MDL 72222 totally blocked the pressure-induced increase in accumbens DA release and the development of LMA, whereas it only reduced the increase in striatal DA release. This suggest that both LMA and the increase of DA release in the nucleus accumbens, but not in the caudate-putamen, could specifically result from a 5-HT3 receptor activation in rats exposed to high pressure.

Sigmoidal admission rate-dependence of toluene narcotic potency in rats: comparison with nitrous oxide.

Aromatic solvents, such as toluene, can cause depression of the central nervous system functions in both solvent-exposed workers and abusers. The mechanism by which toluene produces its effects is generally thought to be similar to that produced by general anaesthetics, including inert gases and alcohols. However, whether lipophilic compounds indirectly influence activity by perturbing membrane lipids or bind directly to proteins remains a major question. In a recent study, the sigmoidal admission rate-dependence of inert gas anaesthetic potency has been suggested to possibly reflect a direct narcotic-protein interaction. Therefore, experiments have been carried out using seven input toluene flows of 0.5, 1, 2, 3, 4, 5 and 6 l/min. Our results indicate that as the rate of toluene delivery increased, the concentration of toluene required to produce anaesthetic effects increased. Although this was fitted relatively well with linear regression, this fitted better when using a sigmoidal model (r = 0.998 vs. r = 0.971, P < 0.01). In addition, comparison with previous data on nitrous oxide shows a striking similarity between plots (r = 0.991) which appears consistent with a similar site of action for both agents. We suggest that all classes of lipophilic agents could produce their inhibitory effects at similar 'non-specific' sites of action of finite size and limited occupancy.

Role of 5-HT1b receptor in the pressure-induced behavioral and neurochemical disorders in rats.

When human divers and experimental animals are exposed to increasing environmental pressure, they develop the high-pressure neurologic syndrome (HPNS) that has been recently demonstrated to include an increase in striatal dopamine (DA) release. This increase has been correlated with enhanced locomotor and motor activity (LMA). In the present study, we investigated the effect of the 5-HT1b receptor antagonist (+/-)cyanopindolol, which has been shown to block at normal pressure the increase in striatal DA release induced by the administration of the 5-HT1b receptor agonist CGS 12066B. Our data clearly showed that the administration of (+/-)cyanopindolol partially blocked both the pressure-induced increase in striatal DA release and the development of LMA. These results suggest the contribution of the 5-HT neurotransmission in the DA-related neurochemical and behavioral disorders that occur in rats exposed to high pressure.