Norbert Balon

Effects of acute hypoxemia on force and surface EMG during sustained handgrip

Data on the consequences of acute hypoxemia on the strength of contraction are often contradictory. In healthy subjects, we tested the effects of hypoxemia (PaO2 = 56 mmHg), maintained for a 30‐min period, on static handgrip elicited by voluntary effort or direct electrical muscle stimulation, in order to separate the consequences of hypoxemia on central or peripheral factors, respectively. Force was measured during maximal voluntary contractions (MVCs), 60% MVCs sustained until exhaustion, and 1‐min periods of electrical muscle stimulation at 60 HZ. The evoked compound muscle action potential (M wave) was recorded in resting muscle and after each period of 60‐HZ stimulation or sustained 60% MVC. Power spectrum analysis of surface electromyogram (EMG) was performed during sustained 60% MVC. Compared to normoxemia, acute hypoxemia lowered MVC (−12%, P < 0.01) but enhanced (+38%, P < 0.01) the peak force elicited by electrical muscle stimulation. In resting muscle, hypoxemia had no influence on the M‐wave amplitude but lengthened the neuromuscular transmission time(+740 μs, P < 0.05). Hypoxemia did not alter the M wave measured after 60 HZ stimulation and 60% MVC. During sustained 60% MVC, hypoxemia markedly depressed the EMG changes, abolishing the leftward shift of power spectra. These data show that acute hypoxemia reduces MVC through depression of the central drive, whereas it improves the peripheral muscle response to electrical stimulation. In addition, hypoxemia reduces the recruitment of slow firing motor unit, which are highly oxygen‐dependent. This could constitute an adaptative muscle response to a reduced oxygen supply.

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.

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.

Nitrogen at Raised Pressure Interacts with the GABAA Receptor to Produce Its Narcotic Pharmacological Effect in the Rat

BackgroundStrong 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. MethodsWe compared the inhibitory and sedative effects of &ggr;-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 GABAA receptor antagonist bicuculline. ResultsIntracerebroventricular GABA infusion up to 60 &mgr;mol 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. ConclusionsThese 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 GABAA 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.

Indirect presynaptic modulation of striatal dopamine release by GABAB 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.

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.