ABSTRACT
Objective: Several studies have shown that the time of day regulates the reinforcing effects of cocaine. Additionally, melatonin and its MT1 and MT2 receptors have been found to participate in modulation of the reinforcing effects of such addictive drugs as cocaine. Loss of the diurnal variation in cocaine-induced locomotor sensitization and cocaine-induced place preference has been identified in pinealectomized mice. In addition, several studies in rodents have shown that administration of melatonin decreased the reinforcing effects of cocaine. The objective of this study was to evaluate the effect of melatonin on cocaine-induced locomotor activity in pinealectomized rats at different times of day (zeitgeber time [ZT]4, ZT10, ZT16, and ZT22). Methods: Naïve, pinealectomized Wistar rats received cocaine at different times of day. Melatonin was administered 30 min before cocaine; luzindole was administered 15 min prior to melatonin and 45 min before cocaine. After administration of each treatment, locomotor activity for each animal was recorded for a total of 30 min. Pinealectomy was confirmed at the end of the experiment through melatonin quantitation by ELISA. Results: Cocaine-induced locomotor activity varied according to the time of day. Continuous lighting and pinealectomy increased cocaine-induced locomotor activity. Melatonin administration decreased cocaine-induced locomotor activity in naïve and pinealectomized rats at different times of day. Luzindole blocked the melatonin-induced reduction in cocaine-induced locomotor activity in pinealectomized rats. Conclusion: Given its ability to mitigate various reinforcing effects of cocaine, melatonin could be a useful therapy for cocaine abuse.
Subject(s)
Humans , Animals , Male , Central Nervous System Depressants/pharmacology , Cocaine-Related Disorders/drug therapy , Pinealectomy , Locomotion/drug effects , Melatonin/pharmacology , Time Factors , Enzyme-Linked Immunosorbent Assay , Random Allocation , Tryptamines/pharmacology , Reproducibility of Results , Circadian Rhythm , Treatment Outcome , Rats, WistarABSTRACT
ABSTRACT The N-salicyloyltryptamine (NST) is an indole derivative compound analogue to the alkaloid N-benzoyltryptamine. In the present study, the antiedematogenic activity of NST was investigated in animal models. Firstly, the acute toxicity for NST was assessed according to the OECD Guideline no. 423. The potential NST-induced antiedematogenic activity was evaluated by carrageenan-induced paw edema in rats, as well as by dextran-, compound 48/80-, histamine-, serotonin-, capsaicine-, and prostaglandin E2-induced paw edema in mice. The effect of NST on compound 48/80-induced ex vivo mast cell degranulation on mice mesenteric bed was investigated. No death or alteration of behavioral parameters was observed after administration of NST (2000 mg/kg, i.p.) during the observation time of 14 days. The NST (100 and 200 mg/kg, i.p.) inhibited the carrageenan-induced edema from the 1st to the 5th hour (**p<0.01; ***p<0.001). The edematogenic activity induced by dextran, compound 48/80, histamine, serotonin, capsaicin, and prostaglandin E2 was inhibited by NST (100 mg/kg, i.p.) throughout the observation period (**p<0.01; ***p<0.001). The pretreatment with NST (50, 100 or 200 mg/kg, i.p) attenuates the compound 48/80-induced mast cell degranulation (**p<0.01; ***p<0.001). Thus, the inhibition of both mast cell degranulation and release of endogenous mediators are probably involved in the NST-induced antiedematogenic effect.
Subject(s)
Animals , Male , Female , Rats , Tryptamines/pharmacology , Salicylates/pharmacology , Edema/drug therapy , Anti-Inflammatory Agents/pharmacology , Peptides/drug effects , Time Factors , Carrageenan , Tryptamines/toxicity , Salicylates/toxicity , Rats, Wistar , Inflammation Mediators , Disease Models, Animal , Edema/chemically induced , Hindlimb , Anti-Inflammatory Agents/toxicityABSTRACT
The influence of melatonin on the developmental pattern of functional nicotinic acetylcholine receptors was investigated in embryonic 8-day-old chick retinal cells in culture. The functional response to acetylcholine was measured in cultured retina cells by microphysiometry. The maximal functional response to acetylcholine increased 2.7 times between the 4th and 5th day in vitro (DIV4, DIV5), while the Bmax value for [125I]-alpha-bungarotoxin was reduced. Despite the presence of alpha8-like immunoreactivity at DIV4, functional responses mediated by alpha-bungarotoxin-sensitive nicotinic acetylcholine receptors were observed only at DIV5. Mecamylamine (100 µM) was essentially without effect at DIV4 and DIV5, while dihydro-ß-erythroidine (10-100 µM) blocked the response to acetylcholine (3.0 nM-2.0 µM) only at DIV4, with no effect at DIV5. Inhibition of melatonin receptors with the antagonist luzindole, or melatonin synthesis by stimulation of D4 dopamine receptors blocked the appearance of the alpha-bungarotoxin-sensitive response at DIV5. Therefore, alpha-bungarotoxin-sensitive receptors were expressed in retinal cells as early as at DIV4, but they reacted to acetylcholine only after DIV5. The development of an alpha-bungarotoxin-sensitive response is dependent on the production of melatonin by the retinal culture. Melatonin, which is produced in a tonic manner by this culture, and is a key hormone in the temporal organization of vertebrates, also potentiates responses mediated by alpha-bungarotoxin-sensitive receptors in rat vas deferens and cerebellum. This common pattern of action on different cell models that express alpha-bungarotoxin-sensitive receptors probably reflects a more general mechanism of regulation of these receptors.