ascorbic-acid and luzindole

Melatonin is a hormone that is critical for normal circadian and seasonal rhythmicity in a wide range of different animals. It is a powerful antioxidant commonly used to prevent reperfusion injury to the heart after infarction. We show here it has other more far-reaching effects on cardiac function. Using the Drosophila model, we show that injection of melatonin increases the regularity of heartbeat significantly and can rescue rhythmicity in flies bearing mutations that adversely affect cardiac function. Notably, melatonin increases cardiac regularity independent of alteration of heart rate. We provide compelling evidence that melatonin's action as an antioxidant is not the mechanism underlying improved cardiac performance. We have strong evidence that melatonin's action on the heart is mediated via a specific G-Protein-coupled receptor encoded by the CG 4313 gene that our results implicate as a candidate melatonin receptor. These results open a line of questioning about fundamental aspects of cardiac pacemaking.

Topics: Animals; Ascorbic Acid; Cardiovascular Physiological Phenomena; Drosophila; Female; Heart; Male; Melatonin; Mutation; Receptors, G-Protein-Coupled; Serotonin; Tryptamines

Serotonin type 2A (5-HT(2A)) receptor-mediated neurotransmitter is known to activate hypothalamic-pituitary-adrenal (HPA) axis, regulate sleep-awake cycle, induce anorexia and hyperthermia. Interaction between melatonin and 5-HT(2A) receptors in the regulation of the sleep-awake cycle and head-twitch response in rat have been reported. Previous studies have shown that melatonin has suppressant effect on HPA axis activation, decreases core body temperature and induces hyperphagia in animals. However, melatonin interaction with 5-HT(2A) receptors in mediation of these actions is not yet reported. We have studied the acute effect of melatonin and its antagonist, luzindole on centrally administered (+/-)-1-(2, 5-dimethoxy-4-iodophenyl) 2-amino propane (DOI; a 5-HT(2A/2C) agonist)-induced activation of HPA axis, hypophagia and hyperthermia in 24-h food-deprived rats. Like ritanserin [(1 mg/kg, i.p.) 5-HT(2A/2C) antagonist], peripherally administered melatonin (1.5 and 3 mg/kg, i.p.) did not affect the food intake, rectal temperature or basal adrenal ascorbic acid level. However, pretreatment of rats with it significantly reversed DOI (10 microgram, intraventricular)-induced anorexia and activation of HPA axis. But the hyperthermia induced by DOI was not sensitive to reversal by melatonin. Mel(1) receptor subtype antagonist luzindole (5 microgram, intraventricular) did not modulate the DOI effect but antagonized the melatonin (3 mg/kg, i.p.) reversal of 5-HT(2A) agonist response. The present data suggest that melatonin reversal of DOI-induced hypophagia could be due to suppression of 5-HT(2A) mediated activation of HPA axis.

Topics: Adrenal Glands; Amphetamines; Animals; Anorexia; Ascorbic Acid; Exploratory Behavior; Feeding Behavior; Fever; Gastrointestinal Transit; Hypothalamo-Hypophyseal System; Injections, Intraperitoneal; Injections, Intraventricular; Male; Melatonin; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Receptors, Cell Surface; Receptors, Cytoplasmic and Nuclear; Receptors, Melatonin; Receptors, Serotonin; Ritanserin; Serotonin Antagonists; Suprachiasmatic Nucleus; Tryptamines