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PubMed2004

Direct effect of melatonin on Syrian hamster testes: melatonin subtype 1a receptors, inhibition of androgen production, and interaction with the local corticotropin-releasing hormone system.

Besides the hypothalamus and pituitary, melatonin action at the testicular level has been recently suggested. Therefore, we investigated in the Syrian hamster, a well-characterized seasonal breeder, melatonin action on Leydig cells, testicular expression of melatonergic receptors, and possible interactions between melatonin receptors and the previously identified testicular serotoninergic and CRH systems. In isolated Leydig cells from active testes of adult hamsters kept in a long-day (14 h light, 10 h dark) photoperiod and from regressed testes of adult animals exposed to a short-day photoperiod during 16 wk (6 h light, 18 h dark), melatonin significantly reduced human chorionic gonadotropin-stimulated production of cAMP and the main androgens: testosterone and androstane-3alpha,17beta-diol, respectively, and decreased the expression of steroidogenic acute regulatory protein, P450 side chain cleavage, 3beta-hydroxysteroid dehydrogenase and 17beta-hydroxysteroid dehydrogenase. In Leydig cells exposed to a short-day photoperiod during 16 wk, melatonin stimulated the conversion of testosterone into 5alpha-reduced androgens by inducing 5alpha-reductase isoform 1, and controlled androstane-3alpha,17beta-diol production by inhibiting 3alpha-hydroxysteroid dehydrogenase expression. Melatonin subtype (mel1a) receptors were detected in Leydig cells. Although the local serotonin system did not mediate melatonin action on androgen production, melatonergic effect on steroidogenesis involved the interaction between mel1a receptors and the inhibitory CRH system. Moreover, melatonin significantly increased CRH mRNA levels and production in hamster Leydig cells expressing CRH subtype 1 receptors. Our studies indicate that melatonin may act as a local inhibitor of human chorionic gonadotropin-stimulated cAMP and androgen production through mel1a receptors, down-regulation of steroidogenic acute regulatory protein, and key steroidogenic enzymes expression and its interaction with the local CRH system.

3-Hydroxysteroid Dehydrogenases↗
PubMed1994

Electric field exposure alters serum melatonin but not pineal melatonin synthesis in male rats.

Sprague-Dawley male rats, maintained in a 14:10 h light:dark cycle were exposed for 30 days (starting at 56 days of age) to a 65 kV/m, 60 Hz electric field or to a sham field for 20 h/day beginning at dark onset. Pineal N-acetyltransferase (NAT), hydroxy-indole-o-methyl transferase (HIOMT), and melatonin as well as serum melatonin were assayed. Preliminary data on unexposed animals indicated that samples obtained 4 h into the dark period would reveal either a phase delay or depression in circadian melatonin synthesis and secretion. Exposure to electric fields for 30 days did not alter the expected nighttime increase in pineal NAT, HIOMT, or melatonin. Serum melatonin levels were also increased at night, but the electric field-exposed animals had lower levels than the sham-exposed animals. Concurrent exposure to red light and the electric field or exposure to the electric field at a different time of the day-night period did not reduce melatonin synthesis. These data do not support the hypothesis that chronic electric field exposure reduces pineal melatonin synthesis in young adult male rats. However, serum melatonin levels were reduced by electric field exposure, suggesting the possibility that degradation or tissue uptake of melatonin is stimulated by exposure to electric fields.

Acetylserotonin O-Methyltransferase↗
PubMed1984

Negative correlation of age and the levels of pineal melatonin, pineal N-acetylserotonin, and serum melatonin in male rats.

Pineal concentrations of N-acetylserotonin and melatonin and serum levels of melatonin were studied in 3-wk-old (prepubertal), 8-wk-old (adult), and 17-mo-old (senile) male rats. They were adapted to a photoperiod of 12 h light/12 h darkness for a minimum of 1 wk and killed at mid-light and mid-dark. Melatonin and N-acetylserotonin were determined by radioimmunoassay. The concentrations of pineal N-acetylserotonin and melatonin were high in the dark period and low in the light period. Statistical analysis indicated that pineal N-acetylserotonin and melatonin levels per 100 gm body weight declined with age. Similarly, serum melatonin demonstrated diurnal changes in all the age groups studied. In addition, there was a significant reduction in the levels of serum melatonin with age. The parallel patterns of decrease in pineal and serum melatonin levels with age suggest a decline in pineal secretion of melatonin in the older animals.

Age Factors↗
PubMed2006

Response of plasma and gastrointestinal melatonin, plasma cortisol and activity rhythms of European sea bass (Dicentrarchus labrax) to dietary supplementation with tryptophan and melatonin.

Melatonin is an effective antioxidant, immunostimulant, gonadal maturating regulator and antistress indoleamine that may be potentially useful for fish farmers. We have explored two possible ways of increasing plasma melatonin levels through the diet: direct melatonin supplementation (ME diet) and supplementation with the melatonin precursor tryptophan (TRP diet). To this end, a group of sea bass was fed a commercial diet (STD diet) at a regular time for 16 days, after which plasma, intestine, and bile samples were taken at four different time points: 120 min before, and 15, 180 and 480 min after feeding. Locomotor activity, intestinal and biliary melatonin, and plasma melatonin, serotonin and cortisol levels were measured. This same sampling process and analyses were also carried out after feeding sea bass TRP diet or ME diet for 1 week. Our results show that melatonin, but not tryptophan supplementation of the diet increases plasma, intestine and bile levels of melatonin. Plasma serotonin levels, on the other hand, were increased by dietary tryptophan, but not by melatonin, confirming the availability of supplemented tryptophan for serotonin synthesis. Both treatments were equally effective in reducing the high cortisol levels observed with the STD diet.

Animals↗
PubMed1989

Effect of environmental temperature and photoperiod on the melatonin levels in the pineal, lateral eye, and plasma of the frog, Rana perezi: importance of ocular melatonin.

Day-night melatonin concentrations were studied in the pineal body, lateral eye, and plasma of the frog Rana perezi in animals maintained in February and July under long (18L:6D) or short (6L:18D) photoperiod and high (25 +/- 1 degree) or low (6 +/- 1 degree) temperature in order to evaluate the influence of these environmental factors. When frogs were kept under short photoperiod and low temperature in February, no melatonin rhythm was observed in the pineal, ocular tissue, and plasma. High temperature at this period of the year induced a day-night rhythm of melatonin levels in the lateral eye and plasma. In July, under long photoperiod and high temperature, animals showed pronounced rhythms of melatonin in the pineal, eye, and plasma. A decrease of environmental temperature in this season abolished the melatonin rhythm. When animals were maintained in August under high (25 +/- 1 degree) temperature and long (18L:6D) or short (6L:18D) photoperiod, the duration of high night time ocular melatonin levels was correlated to the length of the dark phase. In all experiments the high ocular melatonin concentrations and the close parallelism observed between ocular and circulating melatonin profiles suggest that in this species melatonin could be released from the eyes in the general circulation.

Animals↗
PubMed1998

Methylcobalamin amplifies melatonin-induced circadian phase shifts by facilitation of melatonin synthesis in the rat pineal gland.

Effects of methylcobalamin (methyl-B12), a putative drug for treating human circadian rhythm disorders, on the melatonin-induced circadian phase shifts were examined in the rat. An intraperitoneal injection of 1-100 microg/kg melatonin 2-h before the activity onset time (CT 10) induced phase advances of free-running activity rhythms in a dose-dependent manner (ED50=1.3 microg/kg). Injection of methyl-B12 (500 microg/kg) prior to melatonin (1 microg/kg) injection induced larger phase advances than saline preinjected controls, while the injection of methyl-B12 in combination with saline did not induce a phase advance. These results indicate amplification of melatonin-induced phase advances by methyl-B12. Pinealectomy abolished the phase alternating effect of methyl-B12, suggesting a site of action within the pineal gland. In fact, methyl-B12 significantly increased the content of melatonin in the pineal collected 2-h after activity onset (CT 14). In contrast, no difference in melatonin content was found at CT 10, indicating that the effect of methyl-B12 may be gated after the activity onset time when endogenous melatonin synthesis is known to increase. These results suggest that methyl-B12 amplifies melatonin-induced phase advances via an increase in melatonin synthesis during the early subjective night at a point downstream from the clock regulation.

Animals↗
PubMed2000

Melatonin directly scavenges hydrogen peroxide: a potentially new metabolic pathway of melatonin biotransformation.

A potential new metabolic pathway of melatonin biotransformation is described in this investigation. Melatonin was found to directly scavenge hydrogen peroxide (H(2)O(2)) to form N(1)-acetyl-N(2)-formyl-5-methoxykynuramine and, thereafter this compound could be enzymatically converted to N(1)-acetyl-5-methoxykynuramine by catalase. The structures of these kynuramines were identified using proton nuclear magnetic resonance, carbon nuclear magnetic resonance, and mass spectrometry. This is the first report to reveal a possible physiological association between melatonin, H(2)O(2), catalase, and kynuramines. Melatonin scavenges H(2)O(2) in a concentration-dependent manner. This reaction appears to exhibit two distinguishable phases. In the rapid reaction phase, the interaction between melatonin and H(2)O(2) reaches equilibrium rapidly (within 5 s). The rate constant for this phase was calculated to be 2.3 x 10(6) M(-1)s(-1). Thereafter, the relative equilibrium of melatonin and H(2)O(2) was sustained for roughly 1 h, at which time the content of H(2)O(2) decreased gradually over a several hour period, identified as the slow reaction phase. These observations suggest that melatonin, a ubiquitously distributed small nonenzymatic molecule, might serve to directly detoxify H(2)O(2) in living organisms. H(2)O(2) and melatonin are present in all subcellular compartments; thus, presumably, one important function of melatonin may be complementary in function to catalase and glutathione peroxidase in keeping intracellular H(2)O(2) concentrations at steady-state levels.

Catalase↗
PubMed2001

Thrombopoietic properties of 5-methoxytryptamine plus melatonin versus melatonin alone in the treatment of cancer-related thrombocytopenia.

Recent studies have shown that the hematopoietic system is under neuroendocrine control. In particular, thrombopoiesis has been proven to be stimulated by melatonin, and the pineal indole has been shown to be effective in the treatment of thrombocytopenia resulting from different causes. At present, however, there are no data concerning the possible thrombopoietic activity of pineal indoles other than melatonin. The present study was carried out to evaluate the effect of a concomitant administration of the pineal indole 5-methoxytryptamine in patients with cancer-related thrombocytopenia who did not respond to melatonin alone. The present study included 30 patients, who were randomized to receive melatonin alone (20 mg/day orally in the evening) or melatonin plus 5-methoxytryptamine (1 mg/day orally in the early afternoon). A normalization of platelet count was achieved in 5/14 (36%) patients treated with melatonin plus 5-methoxytryptamine and in none of the patients treated with melatonin alone (P < 0.05). Moreover, mean platelet number significantly increased only in the patients treated with melatonin plus 5-methoxytryptamine. This preliminary clinical study would suggest that 5-methoxytryptamine, a pineal indole, may also exert thrombopoietic activity. Further studies, however, will be required to establish whether 5-methoxytryptamine may play a direct thrombopoietic activity, or whether it may act by improving melatonin's efficacy.

5-Methoxytryptamine↗
PubMed2001

Rejuvenation of degenerative thymus by oral melatonin administration and the antagonistic action of melatonin against hydroxyl radical-induced apoptosis of cultured thymocytes in mice.

The effect of melatonin on age-related thymic involution and apoptosis induced by hydroxyl radicals (*OH) in mouse thymocyte cultures was investigated. Exogenous melatonin was administered in the drinking water (15 microg/mL) of 7-month-old male Balb/c mice for 40 consecutive days. Our results show that melatonin distinctly reversed the age-related thymic involution as revealed by the notable increase of cellular density, particularly the number of thymocytes, percentage of thymocytes at G2+S phases and the younger morphological appearance as a whole when compared with control animals. More strikingly, the recovery of these morphometric parameters were maintained for 30 days after the termination of melatonin administration suggesting that the re-established homeostasis by melatonin may last for a longer time. At the same time, when primary culture of thymocytes was preincubated with 200 microM melatonin before their exposure to hydroxyl radicals (*OH) generated by Fe(2+)-mediated Fenton reaction, apoptotic cell death induced by *OH was almost completely prevented as determined by both flow cytometric analysis and the TUNEL assay. DNA laddering assay also documented the inhibition of thymocyte apoptosis by melatonin. Furthermore, we found that the *OH-induced increment of caspase-3 activity in thymocytes was completely abolished by melatonin preincubation. Taken together, our study indicates that in addition to other mechanisms, melatonin may also directly act as an antioxidant via attenuating apoptotic thymocyte death caused by free radicals and stimulates thymocyte proliferation in thymus and thus to rejuvenate the degenerative organ.

Administration, Oral↗
PubMed2005

The formation and properties of the melatonin radical: a photolysis study of melatonin with 248 nm laser light.

The photolysis of melatonin in aqueous solution has been studied spectrometrically with a 248 nm laser. The formation of hydrated electrons in a monophotonic process has been confirmed in neutral solution with a quantum yield of 0.22. Two main absorption bands at 340 and 460 nm plus an absorption shoulder resulted from the counterpart of the ejected electron, a melatonin radical, in solution. The big difference for the relative intensity of the absorption peaks under various pH conditions reveals that the melatonin radical exists in the solution through an acid-base equilibrium. In support from the pH dependence of the spectrum of the intermediate, the pKa1 for the doubly-protonated melatonin radical against the mono-protonated melatonin cation radical was estimated to be -0.95 and the pKa2 for the mono-protonated melatonin cation and melatonin neutral radical was 4.5 +/- 0.5. This work will benefit the basic understanding about melatonin as a UV-light protector, as a light receptor and the antioxidation functions of melatonin.

Electrons↗
PubMed1985

Inhibitory action of exogenous melatonin, 5-methoxytryptamine, and 6-hydroxymelatonin on sexual maturation of male rats: activity of 5-methoxytryptamine might be due to its conversion to melatonin.

The effect on sexual maturation of 6 different pineal indoles, including melatonin, and of the metabolite 6-hydroxymelatonin was studied in the male rat after daily injections from 20 to 40 days of age. Only 5-methoxytryptamine (5MT) and 6-hydroxymelatonin (6M), in addition to melatonin, inhibited the neuroendocrine-reproductive axis during sexual maturation. Their potencies when injected in the afternoon were in the range of one-twentieth to one-fifth that of melatonin. Like melatonin these two indoles had no effect when injected in the morning. N-acetylserotonin, serotonin, 5-hydroxytryptophol and 5-methoxytryptophol did not influence sexual maturation either when injected in the morning or in the afternoon. Chromatographic separation was performed on plasma extracts from rats injected daily with the biologically active indoles and killed 10-120 min after the last injection. This procedure confirmed that 6M injections did not increase plasma melatonin levels. In contrast, plasma melatonin levels in 5MT-treated rats were increased 1 h after the 5MT injection. These results suggest that 5MT or part of it might be acetylated to melatonin; thus inhibition of sexual maturation might be mainly due to melatonin. These results indirectly support the contention that melatonin is the principal pineal indoleamine playing a role during sexual maturation.

5-Methoxytryptamine↗
PubMed1996

Lesions of the melatonin- and androgen-responsive tissue of the dorsomedial nucleus of the hypothalamus block the gonadal response of male Syrian hamsters to programmed infusions of melatonin.

The objective of this study was to characterize a site at which it is likely that melatonin mediates photoperiodic control of reproduction in the male Syrian hamster. The first experiment was a comparison of the distributions of iodomelatonin (IMEL)-binding sites and cells immunoreactive to androgen receptors (AR-ir) in the medio-basal hypothalamus (MBH). AR-ir cells extended throughout the MBH, whereas IMEL binding was restricted to the dorsomedial nucleus (DMN). Comparisons between IMEL binding and AR-ir on adjacent cryostat sections revealed a clear overlap between the IMEL-binding sites and a distinct subpopulation of AR-ir cells within the DMN. The second experiment examined whether lesions of these IMEL- and androgen-responsive cells affected the response of the hamsters to short-day (SD)-like infusions of melatonin. Animals received sham or bilateral electrolytic lesions of the IMEL-binding sites within the DMN of the hypothalamus (MBH-X). Animals were pinealectomized and 4 wk later fitted with an s.c. cannula for the daily infusion of either melatonin (50 ng/h) or saline (500 microliters/10 h). After 6 wk the animals with sham lesions showed gonadal atrophy and lower serum concentrations of LH and prolactin (PRL) after infusions with melatonin. In contrast, MBH-X animals given melatonin had large testes and long-day (LD)-like serum LH concentrations. Infusions of melatonin did, however, cause a significant decline in serum PRL level. This study shows that an intact MBH is essential for the expression of gonadotrophic but not lactotrophic responses to melatonin and/or photoperiod. It also suggests that cells responsive to both gondal steroids and melatonin may be involved in the seasonal variation in GnRH release, and indicates a site at which melatonin might influence sensitivity to steroid feedback, a hypothalamic function known to be regulated by photoperiod.

Androgens↗
PubMed2005

Prediction of melatonin efficacy by pretreatment dim light melatonin onset in children with idiopathic chronic sleep onset insomnia.

Research has shown efficacy of melatonin treatment to advance sleep-wake rhythms in insomnia. In healthy adults, direction and magnitude of the phase shift depends on the timing of administration relative to the phase position of the circadian system. Therefore, in the present study we investigated whether in children with chronic sleep onset insomnia (SOI) efficacy of melatonin treatment in the early evening could be predicted from dim light melatonin onset (DLMO), a phase marker of the circadian system. We combined data of two previously published double blind, randomized, placebo-controlled trials in 110 participants, aged 6-12 years. Sleep was actigraphically estimated, and saliva collected, at baseline and in the third week of a 4-week treatment period with 5 mg melatonin or placebo at 18:00 or 19:00 hours. Primary outcome measures were pre- to post-treatment changes in dim light melatonin onset (DeltaDLMO), sleep onset (DeltaSO), sleep latency (DeltaSL), and total sleep duration (DeltaTSD). Melatonin advanced DLMO with +1:12 h (P < 0.001), SO with +0:42 h (P = 0.004), SL decreased with 25 min (P = 0.019), and TSD did not change significantly, as compared with placebo. In the melatonin-treated group, but not in the placebo-treated group, pretreatment DLMO was significantly related to DeltaDLMO [F(1, 29) = 7.28, P = 0.012] and DeltaSO [F(1, 25) = 7.72, P = 0.010]. The time interval between treatment administration and pretreatment DLMO (INT) was only significantly related to DeltaSO [F(1,26) = 5.40, P = 0.028]. The results suggest that in children with SOI, the efficacy of early evening melatonin to advance sleep onset and endogenous melatonin onset increases the later the pretreatment DLMO is.

Child↗
PubMed1997

Daily melatonin intake resets circadian rhythms of a sighted man with non-24-hour sleep-wake syndrome who lacks the nocturnal melatonin rise.

Effects of daily melatonin intake on the circadian rhythms of sleep and wakefulness, rectal temperature and plasma cortisol were examined in a sighted man who had suffered from the non-24-hour sleep-wake syndrome. The subject lacked the nocturnal melatonin rise in plasma, but showed robust circadian rhythms in rectal temperature and plasma cortisol. The sleep-wake rhythm free-ran with a period longer than 24 hours. Daily melatonin intake at 21:00 h concentrated sleep episodes in the nocturnal period (24:00-8:00 h), and increased the length of the episodes. A single oral dose (3 mg) of melatonin increased plasma melatonin levels to about 1300 pg/mL within one hour and remained at pharmacological levels for approximately 6 hours. The trough of rectal temperature and the circadian rise of plasma cortisol were fixed to the early morning. A higher dose of melatonin (6 mg) did not improve the general feature. After the cessation of melatonin intake, the sleep-wake rhythm began to free-run together with the circadian rhythms in rectal temperature and plasma cortisol. It is concluded that daily intake of melatonin at early night time resets the circadian rhythms in a sighted man who lacked the nocturnal melatonin rise and showed free-running circadian rhythms in routine life.

Administration, Oral↗
PubMed1992

Melatonin increases serotonin N-acetyltransferase activity and decreases dopamine synthesis in light-exposed chick retina: in vivo evidence supporting melatonin-dopamine interaction in retina.

The administration of melatonin, either peripherally (0.01-10 mg/kg) or intraocularly (0.001-10 mumol/eye), to light-exposed chicks dose-dependently increased serotonin N-acetyltransferase (NAT) activity in retina but not in pineal gland. The effect of melatonin was slightly but significantly reduced by luzindole (2-benzyl-N-acetyltryptamine), and not affected by two other purported melatonin antagonists, N-acetyltryptamine and N-(2,4-dinitrophenyl)-5-methoxytryptamine (ML-23). The elevation of the enzyme activity induced by melatonin was substantially stronger than that evoked by 5-hydroxytryptamine, N-acetyl-5-hydroxytryptamine, or 5-methoxytryptamine. The melatonin-evoked rise in the retinal NAT activity was counteracted by two dopamine D2 receptor agonists, quinpirole and apomorphine, and prevented by the dopamine D2 receptor blocker spiroperidol, and by an inhibitor of dopamine synthesis, alpha-methyl-p-tyrosine. Melatonin (0.1-10 mg/kg i.p.) dose-dependently decreased the levels of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC), as well as the DOPAC/dopamine ratio, in chick retina but not in forebrain. The results obtained (1) indicate that melatonin in vivo potently inhibits dopamine synthesis selectively in retina, and (2) suggest that the increase in retinal NAT activity evoked by melatonin in light-exposed chicks is an indirect action of the compound, and results from the disinhibition of the NAT induction process from the dopaminergic (inhibitory) signal. The results provide in vivo evidence supporting the idea (derived on the basis of in vitro findings) that a mutually antagonistic interaction between melatonin and dopamine operates in retinas of living animals.

3,4-Dihydroxyphenylacetic Acid↗
PubMedDate not supplied

Identification of a seasonal elevation in daytime melatonin levels associated with the rut in fallow bucks (Dama dama): the effect of day length and exogenous melatonin.

The timing of the seasonal reduction in voluntary food intake and hormonal changes associated with the rut were investigated in mature fallow bucks subjected to artificial long-day exposure with and without superimposed melatonin-releasing implants. Circulating testosterone profiles and the period of inappetence, signalling the onset of the period of reproductive activity in untreated bucks under natural photoperiod, were phase-advanced in both treatment groups. In the long-day treated group, these profiles were phase-advanced by 1 week, while in the long-day + melatonin group, the phase advance was 6 weeks compared to the controls. Circulating daytime melatonin, elevated in all three groups, corresponds with seasonal changes in circulating testosterone levels associated with the rut. Prolactin profiles followed ambient photoperiod, being high during natural or artificial long days and low during natural short days. Exogenous melatonin administered during long-day exposure initiated a rapid and reversible decrease in circulating prolactin levels. The elevation in plasma melatonin could not be separated temporally from the seasonal testosterone peak by exposure to long days or to exogenous melatonin. However, this daytime melatonin profile was abolished by the ablation of circulating testosterone following immunization against luteinizing hormone releasing hormone (LHRH). The presence of this endogenous melatonin during daylight was observed only during the rut, as measured in two radioimmunoassays and confirmed by mass spectrometry. It is likely that both testosterone and melatonin influence the onset of the seasonal rut in fallow bucks.

Animals↗
PubMed1994

Effects of melatonin on microtubule assembly depend on hormone concentration: role of melatonin as a calmodulin antagonist.

Melatonin may play a key role in cytoskeletal rearrangements through its calmodulin antagonism. In the present work, we tested this hypothesis by studying melatonin effects on both microtubule polymerization in vitro and cytoskeletons in situ. Microtubule assembly is a dynamic process inhibited by Ca2+/calmodulin. Calmodulin antagonists prevent the inhibition by binding to Ca(2+)-activated calmodulin, thus causing microtubule enlargement. In the presence of calmodulin (5 microM) and CaCl2 (1 mM), polymerization at equilibrium was inhibited by 40%. Complete reversal of the Ca2+/calmodulin effect on microtubules was observed with 10(-9) M melatonin or with 10(-5) M trifluoperazine or 1 microgram/ml of compound 48/80. In the absence of Ca2+/calmodulin, melatonin at 10(-5) M inhibited tubulin polymerization like 10(-4) M trifluoperazine does. Melatonin effects on microtubule assembly at both nanomolar and micromolar ranges were corroborated in cytoskeletons in situ. Therefore, it is suggested that at a low concentration (10(-9) M), cytoskeletal melatonin effects are mediated by its antagonism to Ca2+/calmodulin. At a higher concentration (10(-5) M), non-specific binding of melatonin to tubulin occurs, thus overcoming the melatonin antagonism to Ca2+/calmodulin. The results support the hypothesis that under physiological conditions, melatonin synchronizes different body rhythms through cytoskeletal rearrangements mediated by its calmodulin antagonism.

Animals↗
PubMed1996

Exogenous melatonin entrains rhythm and reduces amplitude of endogenous melatonin: an in vivo microdialysis study.

The circadian rhythm of melatonin production was studied using on-line, in vivo microdialysis in the rat pineal gland. With this technique it was possible to record a pronounced melatonin rhythm with very high time resolution. Three phase-markers of the rhythm were calculated from the data, indicating increase (IT50), decrease (DT50) and amplitude of the rhythm. Comparing these phase markers led to several conclusions. Entrainment of the rhythm under constant darkness was performed with melatonin administration at different circadian stages [circadian time (CT) 8 and CT12] and for different periods of time (2 weeks and 4 weeks). Also, entrainment was established by applying 15 min light pulses at CT0. Entrainment of IT50 with melatonin partially uncoupled it from DT50. Four weeks entrainment in constant darkness (DD) caused a phase-delay in DT50 of 2.2 hr. Entrainment of IT50 with light at CT0 for 2 weeks in DD caused a phase-advance in DT50 of 1.3 hr. The entrainment with melatonin was restricted to a narrow window for melatonin to be applied, since injections at CT8 did not result in entrainment. Exogenous melatonin reduced the amplitude of the rhythm of endogenous melatonin. This effect was not circadian time dependent, since administration at CT8 for 2 weeks and at CT12 for 4 weeks resulted in a highly significant decrease. Light did not seem to have an effect on the amplitude. The data presented here provide us with new information about the nature of entrainment by melatonin. Since the present development of melatonergic agents for clinical use focuses on the entrainment capacity, effects of these compounds on amplitude of circadian rhythms needs to be addressed. In vivo microdialysis seems to be a good technique for that.

Animals↗