Argon blocks the expression of locomotor sensitization to amphetamine through antagonism at the vesicular monoamine transporter-2 and mu-opioid receptor in the nucleus accumbens.

We investigated the effects of the noble gas argon on the expression of locomotor sensitization to amphetamine and amphetamine-induced changes in dopamine release and mu-opioid neurotransmission in the nucleus accumbens. We found (1) argon blocked the increase in carrier-mediated dopamine release induced by amphetamine in brain slices, but, in contrast, potentiated the decrease in KCl-evoked dopamine release induced by amphetamine, thereby suggesting that argon inhibited the vesicular monoamine transporter-2; (2) argon blocked the expression of locomotor and mu-opioid neurotransmission sensitization induced by repeated amphetamine administration in a short-term model of sensitization in rats; (3) argon decreased the maximal number of binding sites and increased the dissociation constant of mu-receptors in membrane preparations, thereby indicating that argon is a mu-receptor antagonist; (4) argon blocked the expression of locomotor sensitization and context-dependent locomotor activity induced by repeated administration of amphetamine in a long-term model of sensitization. Taken together, these data indicate that argon could be of potential interest for treating drug addiction and dependence.

A hypothesis regarding possible interactions between the pressure-induced disorders in dopaminergic and amino-acidergic transmission.

When human divers or experimental animals are exposed to high pressure they develop the high pressure neurological syndrome (HPNS). The main symptoms include electroencephalographic changes and behavioral disturbances such as tremor, myoclonia, and hyperlocomotor activity. Recently, pressure-induced disorders in dopaminergic and amino-acidergic neurotransmission have been reported. In the present theoretical study, we review in vitro and in vivo neurochemical, electrophysiological, and pharmacobehavioral evidence concerning alterations in dopaminergic, glutamatergic, and GABAergic transmission occurring at high pressure, and their possible relationship to the symptoms of HPNS. Moreover, we also examine data concerning interactions, at normal pressure, between dopaminergic, glutamatergic, and GABAergic transmission that we suggest they could apply equally under high pressure between the pressure-induced disorders in dopaminergic and amino-acidergic transmission.

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.

Pressure-induced disorders in neurotransmission and spontaneous behavior in rats: an animal model of psychosis.

Disorders in neurotransmission and spontaneous behavior in rats exposed to a high pressure helium-oxygen mixture that shows interesting parallels with the dopaminergic hypothesis of schizophrenia at both the biochemical and the therapeutic responding levels are reviewed. Furthermore, as human subjects exposed to a very high pressure have shown psychotic episodes, we conclude that the pressure-induced disorders in neurotransmission and spontaneous behavior in rats could constitute a valid animal model of schizophreniform psychosis and a useful tool for both the investigation of the biological mechanisms underlying schizophrenia and the development of new antipsychotic drugs.

Blockade of the locomotor stimulant effects of amphetamine by group I, group II, and group III metabotropic glutamate receptor ligands in the rat nucleus accumbens: possible interactions with dopamine receptors.

Previous investigations have shown that mGlu receptors would be involved in the amphetamine-induced motor response. However, data are somewhat controversial across studies where methodological protocols vary. The aim of the present study was to determine the involvement of mGlu receptors in the NAcc in the locomotor-activating properties of amphetamine in rats well habituated to their experimental environment, a condition known to modulate the motor response to amphetamine. Focal infusion of the group I mGlu receptor antagonist S-4-CPG, which has no effect on basal motor activity, virtually suppressed the locomotor response to amphetamine, while infusion of the group II mGlu receptor antagonist LY 341495 or the group III mGlu receptor agonist AP4, at the minimal dose that produces locomotor activation, reduced it by approximately a half. These effects were blocked by the group I mGlu receptor agonist DHPG, the group II mGlu receptor agonist APDC, and the group III mGlu receptor antagonist MPPG, respectively. These data confirm that mGlu receptors in the NAcc contribute to the psychostimulant motor effect of amphetamine. Results are discussed from the view of recent neuropharmacological studies that have defined the effects of these mGlu receptor ligands on basal motor activity and DA receptor agonists-induced locomotor responses in rats exposed to similar experimental procedures (Eur J Neuroscience 13 (2001) 2157; Neuropharmacology 41 (2001) 454; Eur J Neuroscience 13 (2001) 869). It is suggested that the contribution of mGlu receptors to the amphetamine-induced motor response may result mainly from their functional, either direct or indirect, interactions with D1-like receptors in the NAcc.

Differential modulation of the D1-like- and D2-like dopamine receptor-induced locomotor responses by group II metabotropic glutamate receptors in the rat nucleus accumbens.

There is strong evidence for the existence of functional interactions between metabotropic glutamate receptors and dopamine transmission in the nucleus accumbens. In the present study, we investigated the interactions between group II mGlu receptors and D1-like- and D2-like receptors in the rat nucleus accumbens. Administration of the selective group II metabotropic glutamate receptor agonist APDC, which had no effect when injected alone, potentiated the locomotor response produced by the selective D1-like receptor agonist SKF 38393 but had no effect on those induced by the selective D2-like receptor agonist quinpirole (also known as LY 171555)--a compound believed to act only at D2-like presynaptic receptors when injected alone--or co-administration of SKF 38393+quinpirole--a pharmacological condition thought to stimulate both D1-like receptors and presynaptic and postsynaptic D2-like receptors. In contrast, the selective group II mGlu receptor antagonist LY 341495, which induced an increase in basal locomotor activity, showed no effect on the SKF 38393-induced locomotor response, but abolished that produced by quinpirole or SKF 38393+quinpirole. The present findings demonstrate that stimulation of group II mGlu receptors has a cooperative and potentiating action on the locomotor response induced by D1-like receptor activation, whereas blockade of group II mGlu receptors has an antagonist action on the locomotor responses induced by activation of D2-like receptors. Although these data are consistent from a pharmacological point of view, as the effects of the group II mGlu receptor antagonist LY 341495 were blocked by the group II mGlu receptor agonist APDC and conversely, the subtle neurochemical crosstalks underlying such a differential effect of group II mGlu receptors on D1-like- and D2-like DA receptors remain to be elucidated.

Inhibition of the glutamate transporter by L-trans-PDC in the nucleus accumbens prevents the locomotor response to amphetamine.

Infusion in the nucleus accumbens of the glutamate uptake inhibitor L-trans-PDC prevented the amphetamine-induced locomotor response. Since L-trans-PDC has been shown to block the amphetamine-induced increase in glutamate but not in DA release, our result indicates that the glutamate transporter is an obligatory target for the activating properties of amphetamine.

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.

Evidence for inert gas narcosis mechanisms in the occurrence of psychotic-like episodes at pressure environment.

Psychotic-like episodes in divers exposed to high pressure have been attributed to either the high-pressure neurological syndrome, confinement in pressure chamber, the subject's personality, or the addition of nitrogen or hydrogen to the basic helium-oxygen breathing mixture used for deep diving. Alternatively, it is suggested that these disorders are in fact paroxysmal narcotic symptoms that result from the sum of the individual narcotic potencies of each inert gas in the breathing mixture. This hypothesis is tested against a variety of lipid solubility theories of narcosis. The results clearly support the hypothesis and provide new information about the cellular interactions between inert gases at raised pressure and pressure itself.

Evidence for inert gas narcosis mechanisms in the occurrence of psychotic-like episodes at pressure environment.

Psychotic-like episodes in divers exposed to high pressure have been attributed to either the high-pressure neurological syndrome, confinement in pressure chamber, the subject's personality, or the addition of nitrogen or hydrogen to the basic helium-oxygen breathing mixture used for deep diving. Alternatively, it is suggested that these disorders are in fact paroxysmal narcotic symptoms that result from the sum of the individual narcotic potencies of each inert gas in the breathing mixture. This hypothesis is tested against a variety of lipid solubility theories of narcosis. The results clearly support the hypothesis and provide new information about the cellular interactions between inert gases at raised pressure and pressure itself.

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.

Psychomotor skills learning under chronic hypoxia.

Psychomotor deficits are a prominent feature in subjects exposed to hypoxia. Eight subjects exposed to chronic hypoxia during a simulated climb to 8848 m (Everest-Comex 97) were investigated using both a simple psychomotor task (Purdue pegboard) and two complex psychomotor tasks including a recognition task of either a color stimulus (high semantic level) or an abstract sign (low semantic level). Exposure to hypoxic stress mainly produced psychomotor skills learning deficits compared to control study, with greater deficits in the complex psychomotor task. The pattern of results suggests disruptions of motor strategic process. Our data further suggest that the relative strength of implicit or automatic memory processes associated with semantic information processing may increase when disturbances occur in brain functions.

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.

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.

Psychophysiological reactions in humans during an open sea dive to 500 m with a hydrogen-helium-oxygen mixture.

Six commercial divers were investigated for neurological and psychosensorimotor responses during an open sea dive to 500 m with a hydrogen-helium-oxygen mixture containing 49% hydrogen. Results showed only moderate neurological symptoms of high-pressure nervous syndrome, whereas the narcotic effect of hydrogen was detectable, as investigated by psychosensorimotor tests. Nevertheless, the divers successfully carried out the main purpose of the operational dive, which was to prove the feasability of such diving methods by connecting specific elements of an offshore oil installation. Finally, these data support the hypothesis that hydrogen can alleviate some of the symptoms of the high-pressure nervous syndrome and can constitute a useful gas for commercial diving, as it decreases the density of the breathing mixture and therefore improves the living conditions, work, and comfort of the divers. Nevertheless, the present results underscore the relevance of research on individual susceptibility to pressure environment regardless of the composition of the breathing mixture.

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.