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.

Prothrombolytic action of normobaric oxygen given alone or in combination with recombinant tissue-plasminogen activator in a rat model of thromboembolic stroke.

The potential benefit of 100 vol% normobaric oxygen (NBO) for the treatment of acute ischemic stroke patients is still a matter of debate. To advance this critical question, we studied the effects of intraischemic normobaric oxygen alone or in combination with recombinant tissue-plasminogen activator (rtPA) on cerebral blood flow and ischemic brain damage and swelling in a clinically relevant rat model of thromboembolic stroke. We show that NBO provides neuroprotection by achieving cerebral blood flow restoration equivalent to 0.9 mg/kg rtPA through probable direct interaction and facilitation of the fibrinolytic properties of endogenous tPA. In contrast, combined NBO and rtPA has no neuroprotective effect on ischemic brain damage despite producing cerebral blood flow restoration. These results 1) by providing a new mechanism of action of NBO highlight together with previous findings the way by which intraischemic NBO shows beneficial action; 2) suggest that NBO could be an efficient primary care therapeutic intervention for patients eligible for rtPA therapy; 3) indicate that NBO could be an interesting alternative for patients not eligible for rtPA therapy; and 4) caution the use of NBO in combination with rtPA in acute stroke patients.

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.

Nitrogen at raised pressure interacts with the GABA(A) receptor to produce its narcotic pharmacological effect in the rat.

BACKGROUND: Strong evidence supports the concept that conventional anesthetics, including inhalational agents and inert gases, such as xenon and nitrous oxide, interact directly with ion channel neurotransmitter receptors. However, there is no evidence that nitrogen, which only exhibits narcotic potency at increased pressure, may act by a similar mechanism. METHODS: We compared the inhibitory and sedative effects of gamma-aminobutyric acid (GABA) and nitrogen pressure on locomotor activity and striatal dopamine release in freely moving rats and investigated the pharmacologic properties of the GABA-induced and nitrogen pressure-induced narcotic action using the highly selective competitive GABA(A) receptor antagonist bicuculine. RESULTS: Intracerebroventricular GABA infusion up to 60 micromol or exposure to nitrogen pressure up to 3 MPa decreased to a similar extent striatal dopamine release (r2= 0.899, df = 4, P < 0.01) and locomotor activity (r2 = 0.996, df = 28, P < 0.001). However, both agents only showed small effects on striatal dopamine release, reducing dopamine currents by only 12-13% at sedative concentrations. Pretreatment with bicuculline at 0.5, 1, and 2.5 pmol reduced the sedative action of GABA on locomotor activity by 10, 20, and 41%, respectively. Bicuculline in the nanomole range at 1, 2.5, and 5 nmol but not in the picomole range reduced the sedative action of nitrogen pressure by 5, 37, and 73%, respectively. Schild plot analysis is consistent with the fact that bicuculline is a competitive antagonist of both GABA and nitrogen at pressure. CONCLUSIONS: These results suggest (1) that the presynaptic effects of both GABA and nitrogen pressure on striatal dopamine transmission are modest and not mainly involved in their sedative action and (2) that nitrogen at increased pressure may interact directly with the GABA(A) receptor. However, because the antagonistic effect of bicuculline on nitrogen sedation only occurred at much higher bicuculline concentrations than seen with GABA, it is suggested that nitrogen does not compete for the same site as GABA.

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.

The group I metabotropic glutamate receptor antagonist S-4-CPG modulates the locomotor response produced by the activation of D1-like, but not D2-like, dopamine receptors in the rat nucleus accumbens.

Functional interactions between dopamine (DA) and glutamate neurotransmissions in both the dorsal and the ventral striatum have been described for long time. However, there is much controversy as to whether glutamate transmission stimulates or attenuates DA release and locomotor activity. We investigated the functional interactions on locomotor activity between group I metabotropic glutamatergic receptors (mGlu receptors) and both D1-like and D2-like DA receptors in the rat nucleus accumbens. Intra-accumbens administration of the selective group I mGlu receptor antagonist S-4-CPG (0.2 or 2 microg per side), which had no effect when injected alone, prevented the increase in locomotor activity produced by the selective D1-like receptor agonist SKF 38393 (1 microg per side). Co-administration with S-4-CPG of the group I mGlu receptor agonist DHPG, but not of the group II mGlu receptor agonist APDC or the group III mGlu receptor agonist AP4, reversed the antagonistic effect of S-4-CPG on the SKF 38393-induced increase in locomotor activity. This indicates that the antagonistic effect of S-4-CPG could result from an action at the group I mGlu receptors. In contrast, administration of S-4-CPG showed no effect on the locomotor responses produced by either the selective D2-like receptor agonist LY 171555 (1 microg per side) or a mixed solution of SKF 38393 + LY 171555 (1 microg per side each). Altogether, these results confirm that glutamate transmission may control locomotor function through mGlu receptors in a DA-dependent manner, and further indicate that group I mGlu receptors would interact with D1-like receptors, but not D2-like receptors, to modulate DA transmission and locomotor activity.

State-anxiety and low moods: evidence for a single concept.

The aim of the study was to examine the Spielberger's hypothesis, according to which changes in state-anxiety level would correspond exactly to adverse changes in mood states. We analyzed the correlation coefficients between state-anxiety and low moods, and further investigated whether these correlation coefficients increase when mood factors were grouped and added as the Spielberger's hypothesis would suggest. Data were obtained from previous studies performed in eight subjects exposed to hypoxic conditions during a 31-day simulated climb from sea level to 8848 m equivalent altitude in a hypobaric chamber. Adding scores of mood states (by 2, 3, 4, 5, or 6) improved progressively and significantly the correlation coefficient between state-anxiety levels and mood scores when taken individually, up to a maximal increase of 75% of the correlation value when all of the mood factors were added together. The relationship between the number of mood factors by group and the increase in the correlation coefficients between state-anxiety and moods describes a perfect logarithmic regression (r=.9999, n=6, P<.001), that leads to the prediction that 21 mood factors would be needed to define fully the feelings experienced during state-anxiety. This study provides objective evidence for the Spielberger's hypothesis and suggests that low moods and state-anxiety could be arranged in a single concept, and low moods at large regarded as the human feelings experienced during state-anxiety responses. The present relationships were obtained in subjects exposed to stressful environmental hypoxic conditions and should be confirmed for other stressful general conditions.

A study of mood changes and personality during a 31-day period of chronic hypoxia in a hypobaric chamber (Everest-Comex 97).

High altitudes of more than 3,000 meters produce physiological disorders and adverse changes in mood states. In the present study, we report analyses of mood states and personality traits in eight experienced climbers participating in a 31-day period of confinement in hypobaric chamber and gradual decompression from sea level to 8,848 m (Experiment 'Everest-Comex 97'). The subjects were tested at 5,500 m and 6,500 m on Day 13, 5,000 m and 6,500 m on Day 24, and 8,000 m and 8,848 m altitude on Days 27 and 31. Adverse changes in mood states, such as Vigor and Fatigue, occurred at 8,000 m and 8,848 m, which were significantly correlated with cerebral altitude symptomatology. In addition, a significant negative correlation was found between Fatigue and Factor C, which is a personality measure of emotional stability. We suggest that individuals with low emotional stability could be more sensitive to environmental stressors than more emotionally stable subjects who face reality.

Color discrimination under chronic hypoxic conditions (simulated climb "Everest-Comex 97").

Hypoxia is known to alter visual functions. In the present study, the effects of chronic hypobaric hypoxia upon visual color discrimination were studied in 8 subjects participating in a simulated climb from sea level (PO2 = 210 hPa) to 8,848 m (PO2 = 70 hPa) over a 31-day period of confinement in a decompression chamber ('Everst-Comex 97'). During these investigations, the subjects were required to discriminate between colors of different hue in the red, blue, and green ranges. Alterations in color discrimination increased slightly but significantly as altitude increased. Impairments occurred mainly in the red and blue ranges. In addition, our results further indicate that color discrimination would be affected only when a minimum threshold of difference between color stimuli is not present. Methodological and physiological implications are discussed.

Relationships between mood states and performances in reaction time, psychomotor ability, and mental efficiency during a 31-day gradual decompression in a hypobaric chamber from sea level to 8848 m equivalent altitude.

High altitude is characterized by hypoxic environmental conditions that may induce a set of pathological disorders, known as acute mountain sickness. In addition to the physiological symptoms, exposure to high altitude may also produce adverse changes in motor skills, mental efficiency, and mood states, including anxiety. In the present study, we investigated the relationships between mood states, including anxiety, and performance changes in reaction time, psychomotor ability and mental efficiency in eight climbers participating in the 'Everest-Comex 97', a 31-day gradual decompression in a hypobaric chamber from sea level to 8848 m equivalent altitude. Tests of visual reaction time, manual dexterity, and number ordination were used; anxiety responses and mood states were assessed using the Spielberger State-Trait Anxiety Inventory (STAI) and the 'Profile of Mood States' (POMS), respectively. A significant positive correlation was found between the climbers' performance in reaction time and changes in state-type anxiety levels, suggesting that anxiety could lead to an improved reaction time. In addition, significant negative correlations were also found between the climbers' performance in psychomotor ability, mental efficiency, and reaction time, and several POMS factors, including Tension, Hostility, Confusion, and Fatigue. Overall, these data indicate, in agreement with previous studies, that anxiety may favour, or at least not alter, the processes of information of relatively simple tasks, such as reaction time, and further suggest that adverse changes in moods could modulate performance negatively.

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.

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.

An anxiety, personality and altitude symptomatology study during a 31-day period of hypoxia in a hypobaric chamber (experiment 'Everest-Comex 1997').

Extreme environmental situations are useful tools for the investigation of the general processes of adaptation. Among such situations, high altitude of more than 3000 m produces a set of pathological disorders that includes both cerebral (cAS) and respiratory (RAS) altitude symptoms. High altitude exposure further induces anxiety responses and behavioural disturbances. The authors report an investigation on anxiety responses, personality traits, and altitude symptoms (AS) in climbers participating in a 31-day period of confinement and gradual decompression in a hypobaric chamber equivalent to a climb from sea-level to Mount Everest (8848 m altitude). Personality traits, state-trait anxiety, and AS were assessed, using the Cattell 16 Personality Factor questionnaire (16PF), the Spielberger's State-Trait Anxiety Inventory (STAI), and the Lake Louise concensus questionnaire. Results show significant group effect for state-anxiety and AS; state-anxiety and AS increased as altitude increased. They also show that state-type anxiety shows a similar time-course to cAS, but not RAS. Alternatively, our results demonstrate a significant negative correlation between Factor M of the 16PF questionnaire, which is a personality trait that ranges from praxernia to autia. In contrast, no significant correlation was found between personality traits and AS. This suggests that AS could not be predicted using personality traits and further support that personality traits, such as praxernia (happening sensitivity), could play a major role in the occurrence of state-type anxiety responses in extreme environments. In addition, the general processes of coping and adaptation in individuals participating in extreme environmental experiments are discussed.

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.

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.

Personality patterns of anxiety during occupational deep dives with long-term confinement in hyperbaric chamber.

Extreme environments are generally thought to be stressful situations. Occupational deep diving inflicts periods of long-term confinement in hyperbaric chambers and high-pressure exposure on divers. Such extreme environmental conditions have been demonstrated to produce acute responses of anxiety in individual divers. Although these studies have mentioned personality as a factor explaining why some divers reported an increase in ratings of anxiety, the role of personality traits still remains unclear. The present study examines the possible role of personality traits in the development of diving anxiety. Results confirm that diving anxiety remains at the individual level and relatively transient and suggest that personality factors, such as low self-control and emotional instability, that reflect an incapacity to control and express tension in an appropriate manner would play a crucial role in the occurrence of diving anxiety.

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.