6,472 research outputs found
Modafinil: an antinarcoleptic drug with a different neurochemical profile to d-amphetamine and dopamine uptake blockers
No full textTo examine the biochemical differences between modafinil
and dopaminergic-releasing drugs, the purpose of the present
microdialysis study was to compare the effects of modafinil,
d-amphetamine, and dopamine uptake blockers on DA and
GABA release in the rat nucleus accumbens
Modafinil prevents glutamate cytotoxicity in cultured cortical neurons
No full textThe ability of modafinil (Modiodal) to protect cortical neurons from glutamate-induced degeneration was evaluated by measuring electrically evoked [3H]GABA release and [3H]GABA uptake in primary cerebral cortical cultures. In normal cells, electrical stimulation (10 Hz, 2 min) increased [3H]GABA release (FR-NER St1 = 0.77+/-0.14; St2/St1 ratio = 0.94+/-0.02). The exposure of sister cells to glutamate, reduced electrically evoked [3H]GABA release (FR-NER St1 = 0.40+/-0.05; St2/St1 ratio = 0.60+/-0.08). Modafinil (0.3-1 microM) prevented the glutamate-induced reduction of the St2/St1 ratio (0.85+/-0.11; 0.88+/-0.05, respectively). A similar protective effect was observed for [3H]GABA uptake. These findings suggest that modafinil may be neuroprotective in that it attenuates glutamate-induced excitotoxicity in cortical neurons
Preclinical studies with modafinil. Evidence for vigilance enhancement and neuroprotection
No full textModafinil, which is presently used in the treatment of narcolepsy, induces EEG arousal in mammals, including rhesus monkeys and produces behavioral arousal in mice and rats without the induction of stereotyped behaviors. Pharmacological analysis suggests an indirect involvement of central alpha(1)-adrenergic mechanisms but not of dopamine systems in the behavioral activating action of modafinil. Studies on the neurochemical mechanisms of the vigilance promoting actions of modafinil show no or only weak effects on brain monoamides. It is of interest that modafinil can increase glutamine synthase mRNA and protein in various brain regions, suggesting an activation of astrocyte metabolism through wakefulness produced by modafinil and leading to energy production. The major neurochemical action of modafinil, however, appears to be a reduction of GABA release in several brain regions, such as the cerebral cortex and the nucleus accumbens, which is dependent upon 5-HT receptor activation. Increases of dopamine release in the rat nucleus accumbens appears to involve the inactivation of a local GABAergic mechanism. It is postulated that a reduction of GABA release plays a relevant role in the wakefulness produced by modafinil, especially in view of the strong inhibitory regulation by GABA of the excitatory glutamate pathways. Modafinil has also been shown to produce neuroprotective effects in three different types of lesion models, namely a neurotoxic model with MPTP (parkinsonian model), a mechanical trauma model involving partial hemitransection at the di-and telencephalic level, acid a local ischemia model involving ET-1 induced injury. Modafinil will therefore be of clinical relevance not only in sleep disorders but could also find potential applications in the treatment of neurodegenerative diseases such as Parkinson's disease and stroke
The effects of modafinil on striatal, pallidal and nigral GABA and glutamate release in the conscious rat: evidence for a preferential inhibition of striato-pallidal GABA transmission.
No full textThe effects of the anti-narcoleptic drug modafinil (30-300 mg/kg i.p.) on GABA and glutamate release were evaluated in the basal ganglia of the conscious rat, by using the microdialysis technique. Modafinil (100 mg/kg) inhibited striatal (85+/-4% of basal values) and pallidal (85+/-2%) GABA release without influencing local glutamate release. At the highest dose (300 mg/kg), modafinil induced a further reduction of pallidal (75+/-2%) but not striatal (82+/-7%) GABA release and increased striatal (134+/-11%) but not pallidal glutamate release. On the contrary, in the substantia nigra modafinil reduced GABA release only at the 300 mg/kg dose (59+/-5%) without affecting glutamate release. The preferential reduction in striato-pallidal GABA release at the 100 mg/kg dose of modafinil suggests that modafinil may be useful in the treatment of Parkinsonian diseases
Circé // Intermède en un acte, par // J.n-B.te Rousseau // mis en Musique // Par M. R** // Représenté // pour la premiere // fois à Marseille // le [ ] juillet 1790
No full textAncien possesseur : Thibault, Geneviève (1902-1975). Ancien possesseurTitre uniforme : Rambert (17..-1... ; compositeur). Compositeur. [Circé]Titre dans un encadrement gravé "Gius. Poggiali sc." avec adresse "Vendesi da Gaetano Barchesi libraio nella Condotta in Firenze", collé sur la garde de début. Le nom "Rambert" figure en bas à droite de la p. de titre. - Lieu et date de représentation d'une autre encre, de la même main que le nom du compositeur. - Compositeur identifié d'après Léandre Moreau, Histoire du théâtre à Marseille : le Grand-théâtre (1792-1793), 1872, p. 30. - Librettiste non identifié ; les scènes 6 et 8 reprennent les 2 airs de la cantate "Circé" de Jean-Baptiste Rousseau et en paraphrasent les récitatifs. - Rôles : une femme (Ut 1), Circé (Ut 1), un homme de la suite de Circé (Fa 4), 2 coriphées (Fa 4), Ulisse (Fa 4), Pluton (Fa 4). - Choeur : Ut 1 (2) ; haute-contre (Ut 3), taille (Ut 4), basse-taille (Fa 4), une voix derrière le théâtre (Fa 4). - Vl 2, vla, fl picc, fl 2, ob 2, clar 2 (en ut, si b), cor 2 (en ré, mi, si b, mi b), fag, trb, b, bc, timp (en ré). - La partie de timb de l'ouverture est notée séparément à la suite (p. 14). - Ratures et indications de coupures, peut-être pour la reprise de janvier 1793 ; 4 p. non numérotées sur papier bleuté insérées après la p. 94, pour remplacer le contenu des p. 91-94Présentation musicale : [Partition]Appartient à l’ensemble documentaire : RISM2Appartient à l’ensemble documentaire : Chambure1Appartient à l’ensemble documentaire : RISMMssIntermèdes français -- +* 1700......- 1799......+:18e siècle:Opéras -- +* 1700......- 1799......+:18e siècle
Modafinil and cortical γ-aminobutyric acid outflow. Modulation by 5-hydroxytryptamine neurotoxins
No full textThe acute or chronic administration of modafinil, (diphenyl-methyl-sulfinyl-2-acetamide, 30 mg/kg s.c.) decreased gamma-amino-butyric acid (GABA) outflow from the cerebral cortex of freely moving guinea pigs and rats. In 5,7-dihydroxytryptamine intracerebroventricularly pretreated guinea pigs, the effect of modafinil on GABA outflow was reversed and the noradrenaline cortical levels increased. Prazosin (35.8 ng/kg i.p.) blocked the drug-induced increase in GABA efflux. In vitro experiments, performed in rat cortical slices, showed that modafinil failed to affect [3H]GABA release and uptake as well as glutamic acid decarboxylase activity. In conclusion, our results suggest that the balance between central noradrenaline and 5-hydroxytryptamine transmission is important for the regulation by modafinil of the GABAergic release in the cerebral cortex
Reduced sensitivity of fa/fa Zucker rats to adrenomedullin
No full textRat adrenomedullin is a peptide vasodepressor that may be of importance in the pathogenesis of hypertensive disease. Because of the known link between obesity and hypertension, we hypothesized that decreased responsiveness to adrenomedullin might be seen in an obese rodent model. In this study, the in vivo vasodilator actions of exogenous adrenomedullin were compared in anesthetized lean (n = 7) and obese (fa/fa) Zucker rats (n = 8). Adrenomedullin dose dependently lowered mean arterial pressure in both phenotypes, but the half-maximal dose (ID50) was 2-fold higher in fa/fa rats (1.7 +/- 0.22 vs. 0.83 +/- 0.06 nmol/kg). Moreover, the duration of effect was markedly reduced in the fa/fa rats, to 1-2 min from about 5 min in the lean animals. There was no evidence for an increased rate of degradation of adrenomedullin in the fa/fa rats. Although the rats used in this study were not hypertensive, adrenomedullin had reduced sensitivity and duration of action. The evidence suggests possible defects at the target receptor or altered metabolism of adrenomedullin in obesity.LR: 20061115; PUBM: Print; JID: 0372712; 0 (Peptides); 0 (Vasodilator Agents); 148498-78-6 (Adrenomedullin); ppublishSource type: Electronic(1
Identification of biochemical defects in pancreatic islets of fa/fa rats: a developmental study
No full textAdult obese (fa/fa) Zucker rats hypersecrete insulin in response to glucose and other secretagogues. Functional changes in islet alpha 2-adrenoceptors (8) and glycolytic regulation (9) have been reported. In this study, the development of these biochemical lesions in islets isolated from suckling (3 week old) and weanling (5 week old) lean and fa/fa rats was investigated and compared to results in adult animals. Glucose (15 mM)-induced insulin secretion was inhibited by mannoheptulose (MH) in lean (n = 8) but not fa/fa (n = 10) adult rats, indicating loss of sensitivity of glucokinase to competitive inhibition. Sensitivity to MH was somewhat reduced in the islets of 3- and 5-week-old fa/fa (n = 7 and 12) compared to lean (n = 15 and 9) rats, requiring 30-100 fold higher concentrations to achieve significant inhibition. At 3 weeks of age fa/fa rats did not differ from lean controls in either islet insulin content or body weight, but both parameters were increased in fa/fa rats by 5 weeks. The presence of altered alpha 2-adrenoceptor function in fa/fa rats could not be confirmed in this study. Unlike the previous report, prazosin did not antagonize alpha 2-agonist mediated inhibition of insulin secretion. The presence of defective regulation of the glycolytic pathway by mannoheptulose in suckling and weanling rats may contribute to development of hyperinsulinemia in fa/fa rats.LR: 20061115; PUBM: Print; JID: 9305691; 0 (Receptors, Adrenergic, alpha); 11061-68-0 (Insulin); 50-99-7 (Glucose); 654-29-5 (Mannoheptulose); EC 2.7.1.2 (Glucokinase); ppublishSource type: Electronic(1
Effect of adrenalectomy on the development of a pancreatic islet lesion in fa/fa rats
No full textAdrenalectomy prevents development of obesity and hyperinsulinaemia in obese (fa/fa) Zucker rats, thereby implicating the hypothalamo- pituitary-adrenal axis in the pathogenesis of obesity. In this study glucose-induced insulin secretion and glucokinase activity were investigated in isolated islets from adrenalectomized and control obese and lean female rats. Islets from control fa/fa rats were more sensitive to glucose with a half-maximal effective concentration (EC50) of 6.1 +/- 2.0 mmol. 1(-1) compared with 10.6 +/- 2.7 mmol. 1(-1) for adrenalectomized fa/fa rat islets. Adrenalectomy did not alter the islet sensitivity to glucose in the lean rats (EC50 of 9.4 +/- 1.5 mmol.1(-1) and 9.3 +/- 2.0 mmol. 1(-1) for adrenalectomized and control lean rats respectively). Mannoheptulose did not inhibit insulin secretion from control obese rats; however at concentrations of 1.0 mmol. 1(-1) or more it significantly inhibited glucose-induced insulin secretion in adrenalectomized obese and lean, and control lean rat islets (P < 0.05). In adrenalectomized fa/fa islets the glucokinase Km was increased twofold compared with the control fa/fa rats (9.5 +/- 1.5 mmol. 1(-1) vs 5.0 +/- 1.5 mmol. 1(-1), respectively), but there was no significant change in glucokinase Km in the lean rat islets after adrenalectomy. Mannoheptulose (10 mmol.1(-1) caused a significant reduction in glucose phosphorylation in disrupted islets of adrenalectomized fa/fa and lean, and of control lean rats, but not of control fa/fa rats. These data demonstrate that development of abnormal regulation of glycolysis in pancreatic islet beta cells of fa/fa rats, as indicated by the insulin response to manno-heptulose and glucokinase activity, is dependent on an intact hypothalamo-pituitary-adrenal axis.LR: 20061115; PUBM: Print; JID: 0006777; 0 (Blood Glucose); 11061-68-0 (Insulin); 50-22-6 (Corticosterone); 50-99-7 (Glucose); 654-29-5 (Mannoheptulose); EC 2.7.1.1 (Hexokinase); EC 2.7.1.2 (Glucokinase); ppublishSource type: Electronic(1
Ultrastructural and secretory heterogeneity of fa/fa (Zucker) rat islets
No full textMany previous studies of obese rodents documented biochemical changes in pancreatic islets that contribute to hyperinsulinemia in vivo. Those studies used heterogeneous populations of islets, although the size of islets from obese rats ranges from 500 microm. Here, functional and morphological changes in size-sorted ( 250 microm diameter) islets from obese Zucker (fa/fa) rats were correlated. Ultrastructural examination revealed that > 250 microm cultured islets had an increased number of immature secretory granules in the beta cells. The number of degranulated beta cells in > 250 and 250 microm, 250 microm islets compared with small islets. Studies of individual beta cells by reverse hemolytic plaque assay revealed 3-fold more cells from > 250 microm islets were stimulated by 1.4 mmol.l(-1) glucose than cells from < 125 microm islets. We conclude that functional defects in mixed size populations of islets from fa/fa rats are mainly due to alterations in the large islets, whereas smaller islets have relatively normal function. Exposure to high glucose exacerbates morphological and functional differences of large islets, which could have important implications in the transition to noninsulin-dependent diabetes when beta cell insulin production is unable to compensate for hyperglycemia.LR: 20061115; PUBM: Print; JID: 7500844; 11061-68-0 (Insulin); 50-99-7 (Glucose); 654-29-5 (Mannoheptulose); 7782-44-7 (Oxygen); ppublishSource type: Electronic(1
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