Biomedical subjects
R Boulu
Publications and source records attributed to R Boulu.
[Behavioral and neurochemical methods in research on new psychotropics].
Since the discovery of the antipsychotic effects of chlorpromazine by the French psychiatrists DELAY and DENIKER in 1952, preclinical pharmacologists have proposed several laboratory tests, that have been used to demonstrate the potential activity of drugs in the treatment of mental disorders including schizophrenia, depressive illness and anxiety. Tests are divided into behavioural tests and neurochemical tests. Electrophysiology tests are not considered in this paper. Concerning schizophrenia, although there is no valid model, behavioural tests presently used are: antagonism against various responses induced by dopamine receptor agonists, inhibition of conditioned behaviours, latent inhibition, startle reaction, models related to the neurodevelopmental hypothesis. For antidepressant activity, models are based on antagonism of various effects of reserpine. More anthropomorphic models involve helplessness behaviours, social isolation, changes induced by limbic system lesions. Biochemical investigations mainly involve in vitro and in vivo tests: study of changes in the metabolism of neurotransmitters using microdialysis and other procedures, interaction with receptor subtypes. As a result of advances in molecular biology, other tools are now emerging, but classical tests remain useful.
Extracellular glutamate during focal cerebral ischaemia in rats: time course and calcium dependency.
The time course of changes in extracellular glutamic acid levels and their Ca2+ dependency were studied in the rat striatum during focal cerebral ischaemia, using microdialysis. Ischaemia-induced changes were compared with those produced by high K(+)-evoked local depolarization. To optimize time resolution, glutamate was analysed continuously as the dialysate emerged from the microdialysis probe by either enzyme fluorimetry or biosensor. The Ca2+ dependency of glutamate changes was examined by perfusing the probe with Ca(2+)-free medium. With normal artificial CSF, ischaemia produced a biphasic increase in extracellular glutamate, which started from the onset of ischaemia. During the first phase lasting approximately 10 min, dialysate glutamate level increased from 5.8 +/- 0.9 microM.min-1 to 35.8 +/- 6.2 microM where it stabilized for approximately 3 min. During the second phase dialysate glutamate increased progressively to its maximum (82 +/- 8 microM), reached after 55 min of ischaemia, where it remained for as long as it was recorded (3 h). The overall changes in extracellular glutamate were similar when Ca2+ was omitted from the perfusion medium, except that the first phase was no longer detectable and, early in ischaemia, extracellular glutamate increased at a significantly slower rate than in the control group (2.2 +/- 1 microM.min-1; p < 0.05). On the basis of these data, we propose that most of the glutamate released in the extracellular space in severe ischaemia is of metabolic origin, probably originating from both neurons and glia, and caused by altered glutamate uptake mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)
Involvement of dopaminergic receptors in quinolinate-induced striatal lesions.
The purpose of this study was to examine the effects of blockade (sulpiride) and activation (quinpirole) of dopaminergic D2 (DA2) receptors on brain lesions subsequent to excessive activation of glutamate (GLU) receptors. Striatal lesions were produced by direct injection of quinolinic acid, an endogenous GLU receptor agonist. Sulpiride (100 mg kg-1 i.p., 30 min before quinolinic acid injection and 1 h after) significantly (p < or = 0.05) reduced the volume of the lesion by around 20%. Quinpirole (1.25 mg kg-1 i.p., 30 min before quinolinic acid injection) had no effect. The protective action of DA2 receptor blockade strongly suggests that quinolinic acid-induced excitotoxicity may be partly modulated by DA2 receptors.
Brain weight and noradrenaline content in mice selected for low (MGL) and high (MGH) blood magnesium.
Brain noradrenaline content was determined by high performance liquid chromatography in adult male mice from three different strains: 40 mice with genetically low (MGL) or high (MGH) blood magnesium levels, obtained by selective breeding and 20 outbred Swiss albino mice. Brain wet weight and noradrenaline levels were significantly higher in MGL than in MGH and Swiss mice. Few or no differences were found between MGH and Swiss mice. MGL and MGH animals had a similar mean body weight, were raised in identical conditions, and were fed with a normal diet, rich in magnesium. These results together with the higher urinary noradrenaline excretion previously observed in the MGL line, indicate that the mere selection for genetic traits inducing low blood magnesium levels entails an increased catecholamine production. This phenomenon most probably accounts for the higher sensitivity and/or reactivity of MGL animals to stress. The possible role of magnesium-controlling genetic factors in the regulation of brain growth is also suggested.
High cardiac zinc levels in spontaneously hypertensive rats.
OBJECTIVES: Higher cardiac zinc levels have been observed previously in spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto (WKY) rats. However, this difference was established in adult males only and needed to be confirmed on a larger number of animals of both sexes. We also explored the respective roles of genetic and environmental factors in the genesis of this zinc anomaly as well as the causal relations with hypertension. DESIGN: Cardiac zinc levels were determined in adult male and female SHR and WKY rats originating from various colonies and submitted to various experimental conditions (anaesthesia, stress). These determinations were also performed in 3-week prehypertensive SHR and in adult Wistar rats submitted or not to deoxycorticosterone acetate-salt-induced hypertension. METHOD: Zinc levels were measured by flame atomic absorption spectrophotometry. RESULTS: In adults, cardiac zinc content was significantly higher in SHR than in WKY rats irrespective of sex and experimental conditions. In young prehypertensive rats, the difference between SHR and WKY cardiac zinc levels was also very significant. Experimental hypertension induced in Wistar rats did not entail any significant rise in cardiac zinc levels. CONCLUSIONS: These findings indicated that the higher cardiac zinc of SHR is not secondary to blood pressure elevation. High erythrocyte zinc, previously described in SHR, together with the present data suggest the occurrence of a primary genetic defect leading to high intracellular zinc in SHR. The possible role of this zinc anomaly in the development of hypertension and/or cardiac hyperplasia is discussed.
[Experimental antithrombotic activity of oral isosorbide dinitrate].
The activity of isosorbide dinitrate (ISDN) a nitrate derivative with platelet anti-aggregant properties, was studied on a model of arterial thrombosis by electric stimulation of the rat carotid arteries. In control animals, occlusive thrombosis occurred in 15.3 +/- 1.0 minutes. When administered orally in dosages of 1 to 30 mg/kg, 30 minutes before stimulation, ISDN prolonged the time to arterial occlusion by a factor of 2 to 3 times. This effect was significant from doses of 1 mg/kg. This anti-thrombotic activity was unchanged by pretreatment of 100 mg/kg I.V. of acetylsalicylic acid, a dose sufficient to inhibit prostacycline synthesis. On the other hand, its activity was completely blocked by the administration of an inhibitor of NO-synthetase, L-nitroarginine methylester (1 mg/kg I.V.). These results show that ISDN is active on a model of arterial thrombosis in the rat by a mechanism independent of prostacycline production but implying a stimulation of the formation of nitric oxide.
Oral administration of isosorbide dinitrate inhibits arterial thrombosis in rats.
The effect of isosorbide dinitrate, a nitrovasodilator known to inhibit platelet function, was examined in a model of electrically induced carotid artery thrombosis in rats. In the dose range of 1-30 mg/kg isosorbide dinitrate, administered orally, significantly delayed carotid occlusion. These results demonstrate that isosorbide dinitrate has antithrombotic activity and it is suggested that this antithrombotic activity is due to the generation of nitric oxide.
Lesioning the substantia nigra reduces striatal infarct volume following focal ischemia in rats.
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hypobaric hypoxia: central catecholamine levels and cortical PO2 and avoidance response in rats treated with apomorphine.
The learning of a conditioned avoidance response, the catecholamine levels in some cerebral structures, and the evolution of the cortical PO2, were studied under hypobaric hypoxia (300 torr) and under normoxia, in rats treated or not with apomorphine, at the dose of 1 or 10 mg/kg i.p. Apomorphine at 1 mg/kg improves the learning capacity and stabilises the cerebral catecholamine levels under hypoxia; no modification of the evolution of the cortical PO2 during hypoxia was observed between control rats and rats treated with this dose of apomorphine. Apomorphine at 10 mg/kg totally inhibits learning under normoxia or hypoxia. It is therefore possible to suppose that the antihypoxic protective mechanism of low-dose apomorphine is due to a stabilization of the levels of both dopamine and noradrenaline during hypoxia, but not to an increase in the cerebral oxygen availability. These data suggest the clinical possibility of using other dopaminergic stimulating agents for their eventual antihypoxic properties.
[Effects of dihydroergocriptine, a dihydrogenated ergot alkaloid, on cutaneous or visceral capillaries (author's transl)].
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[Effect of dibutyryl cyclic AMP on cerebral energy charge and electrocorticographic activity in rats under asphyxic hypoxia].
In Rats anesthetized with pentobarbital and submitted to brief asphyxic episodes, intracerebroventricular administration of dibutyryl cyclic AMP inhibits the decrease of energy charge, delays the disappearance of electrocorticographic activity (E Co G) and shortens the recovery time of E Co G.
Cerebral metabolic, hemodynamic and antihypoxic properties of l-eburnamonine.
l-Eburnamonine--16-oxoeburnane--assumes experimental cerebral 'oxygenator' and antihypoxic properties which appear more pronounced than those of vincamine. In anesthetized dogs, l-eburnamonine increases the cerebral oxygen supply and the cerebral oxygen consumption, without cerebral vasodilation; l-eburnamonine improves the cerebral capillary circulation, as observed on the rheoencephalogram. l-Eburnamonine inhibits the effects of hypobaric hypoxia in mice (increase of survival time) and in rats (inhibition of amnesic effects of hypoxia). l-Eburnamonine decreases the electroencephalographic consequences of the acute and iterative asphyxic anoxia in curarized rats and, by means of the protection of the cerebral cortex, inhibits the postischemic increase of thalamic somesthetic evoked potentials in curarized cats. Further studies are necessary to precise the mechanisms involved in these 'cerebral protective' properties of l-eburnamonine.
[Effects of various dopaminergic agonists on the pO2 of the cerebral cortex].
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[Behavior modifications induced by unilateral administration of picrotoxin into rat substantia nigra].
Intranigral injection of picrotoxin in Rats induced contralateral rotation and stereotyped behaviour. These responses were significantly altered following neuroleptic treatment (haloperiod, pimozide) or ipsilateral striatal electrolytic destruction. The present results provide behavioural evidence for gamma-aminobutyric acid-mediated inhibition of the dopaminergic nigrostriatal pathway.
[Increase in the oxygen available to the cerebral cortex after the administration of carbonic anhydrase inhibitors].
Oxygen tension (pO2) in cerebral cortex was measured by polarographic method in unanesthetized rabbits. Intravenous administration (25 mg/kg) of carbonic anhydrase inhibitors (acetazolamide, methazolamide, dichlorphenamide, sulthiame) induced an early important rise of cortical p O2, which is not dependent on increase of p O2 and p CO2 and decrease of pH in arterial blood. High dosage of acetazolamide (250 mg/kg) produced the same effect and did not suppress the increase of cortical p O2 under air-CO2 inhalation. This result suggests that CO2 might act specifically upon cerebral vessels.
[Psychopharmacology of tryptophan (author's transl)].
L-tryptophan is a widely distributed aminoacid, the metabolic pathways of which include serotonin synthesis. Many authors have studied the effects of tryptophan upon the central nervous system in man and animals since serotonin is considered as a neurotransmitter. The most promising results are related to the treatment of depressive disorders. It could be assumed that a better understanding of the role of serotonin and other tryptophan metabolites would presumably lead to further clinical applications.
Clofibrate treatment of hyperlipidemia in chronic renal failure.
The pharmacokinetics of the hypolipidemic agent, clofibrate have been studied in anuric patients on intermittent hemodialysis. In addition we have tried to determine whether the treatment of hyperlipidemia of chronic renal failure with clofibrate was safe and efficacious. Seven healthy volunteers and five uremic patients received a single dose of 25 mg/kg body weight of clofibrate. Mean peak plasma levels of clofibrate were comparable in both groups and were reached 3.5 hr after drug ingestion in the control subjects and after 6.5 hr in the uremic patients. The mean plasma half-life of clofibrate was 16.7 hr and 68.4 hr in the control subjects and in the patients, respectively (P less than 0.001). Following a short loading period a daily oral maintenance dose of 5 mg/kg body weight was given leading to a plasma clofibrate level of 75-100 microgram/100 ml. Five hyperlipidemic uremic patients received this dose for 3 months. Their plasma clofibrate and creatine kinase levels were constantly monitoried to detect clofibrate myotoxicity which we have observed in uremic patients at plasma levels generally considered safe in patients with normal renal function. Significant decreases in serum total lipid, triglyceride, and cholesterol levels were observed when compared to pretreatment values. In two of the 5 patients serum lipids remained decreased for 10 and 14 months. It is concluded that clofibrate treatment of hyperlipidemia in uremic patients, when carefully monitored, is safe and efficacious.