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In its role as a pineal hormone, melatonin is a pleiotropic, nocturnally peaking and systemically acting chronobiotic. These effects are largely explained by actions via G protein-coupled membrane receptors found in the suprachiasmatic nucleus, but also in numerous other sites. Nuclear (ROR/RZR), cytoplasmic (quinone reductase-2, calmodulin, calreticulin) and mitochondrial binding sites and radical-scavenging properties contribute to the actions of melatonin. Regulation of pineal melatonin biosynthesis is largely explained by control mechanisms acting on arylalkylamine N-acetyltransferase, at the levels of gene expression and/or enzyme stability influenced by phosphorylation and interaction with 14-3-3 proteins. Melatonin is not only a hormone but is also synthesized in numerous extrapineal sites, in which it sometimes attains much higher quantities than in the pineal and the circulation. It is also present in many taxonomically distant groups of organisms, including bacteria, fungi, and plants. Moreover, melatonin is a source of bioactive metabolites, such as 5-methoxytryptamine, N 1-acetyl- N 2-formyl-5-methoxykynuramine and N 1-acetyl-5-methoxykynuramine. [ABSTRACT FROM AUTHOR]

The 5-hydroxytryptamine (5HT) receptor agonist, 5-methoxytryptamine, inhibited in a concentration-dependent manner the electrically-evoked release of H-5HT from superfused rat hypothalamic slices, with an IC of 560 nmol/l, without affecting the spontaneous outflow of radioactivity. In the presence of the selective monoamine oxidase B (MAO B) inhibitor, (−)-deprenyl (1 μmol/l), the concentration-effect curve for 5-methoxytryptamine was shifted significantly to the left, and the IC was decreased to 25 nmol/l. Under the same experimental conditions, the potency of the 5HT receptor agonist lysergic acid diethylamide (LSD) at inhibiting the electrically-evoked release of H-5HT was the same in the presence as well as in the absence of (−)-deprenyl. The IC values for LSD were 34 nmol/l in the absence of deprenyl, and 31 nmol/l in the presence of the MAO B inhibitor. It is concluded that deprenyl potentiates the inhibition by 5-methoxytryptamine of H-5HT release, by preventing its inactivation through MAO B. Since 5-methoxytryptamine may be present in the pineal gland of some species, the potent effects of this 5-HT receptor agonist on seretoninergic neutrotransmission may be of physiological relevance. [ABSTRACT FROM AUTHOR]

The effects of different 5-methoxyindoles on the process of protein/peptide secretion characterized by the formation of granular vesicles (GV) have been studied in mouse pinealocytes maintained in explant culture. All 5-methoxyindoles studied clearly influence the number of granular vesicles in the pinealocytes. Comparing all present results it appeared that, in this system, melatonin was the least effective of all 5-methoxyindoles tested in stimulating secretion. 5-Methoxyindole-3-acetic acid, irrespective of the duration of the experiment and of the presence of noradrenaline, increased the number of GV. For all other 5-methoxyindoles, 5-methoxytryptamine, 5-methoxytryptophan, 5-methoxytryptophol and melatonin, it appeared that the effects depend on the duration of application and on the presence or absence of noradrenaline in the medium. Moreover, depending on the experimental conditions and the 5-methoxyindole tested, antagonistic as well as synergistic effects between 5-methoxyindoles and noradrenaline were observed. The present results, which suggest that the 5-methoxyindoles are also active in the pineal gland itself, demonstrate that, as far as the formation of granular vesicles is concerned, there exists a very complex mechanism of regulation, involving the sympathetic innervation and the 5-methoxyindoles (which are themselves under the influence of this innervation). The physiological significance of this system is discussed in relation to a proposed working hypothesis. [ABSTRACT FROM AUTHOR]

5-Hydroxytryptamine (5-HT) stimulated an increase in short-circuit current (I) in guinea-pig isolated ileal mucosa over a wide concentration range (0.1 nM-0.1 mM). The concentration-response relationship was biphasic, consisting of a high potency phase (0.1 nM-1 μM) and a low potency phase (3-10 μM). Stimulation of Isc observed at the high potency phase tended to be sustained while responses at the low potency phase (3-10 μM) contained two components, an initial 'transient' response followed by a 'maintained' response. Both the high potency phase (maximum stimulation ∼30 μA cm) and the low potency phase (maximum stimulation ∼80 μA cm ) 5-HT response were antagonized by tetrodotoxin (TTX, 0.3 μM) and atropine (1 μM). However, another low potency (3 μM-0.1 mM, maximum stimulation ∼30 μA cm) component of the 5-HT response was revealed in the presence of TTX or atropine. In the presence of methysergide (1 μM), the concentration-response relationship of 5-HT was still biphasic and tropisetron (0.1 and 10 μM) antagonized both phases of the 5-HT response. In the presence of methysergide, the high potency phase 5-HT response was mimicked by 5-methoxytryptamine (5-MeOT) and the selective 5-HT agonist SC-53116 but not by BIMU 8. The potent 5-HT antagonist GR 113808 antagonized the response to 5-MeOT in a surmountable manner with an affinity estimate of 9.6 ± 0.3 ( n = 4). The 5-MeOT stimulated increase in I was also antagonized in an unsurmountable manner by granisetron (1 μM). In the presence of methysergide, desensitization of 5-HT receptors with 2-methyl-5-hydroxytryptamine (10 μM) abolished both phases of the 5-HT response. Under the same condition, desensitization of 5-HT receptors with 5-MeOT (10 μM) abolished only the high potency 5-HT response and dextrally shifted the low potency 5-HT response. These data show that neuronal and non-neuronal 5-HT receptors are involved in the regulation of secretion in ileal mucosa. We propose the presence of a neuronal 5-HT receptor located upstream of the well characterized neuronal 5-HT receptors to be responsible for the high potency 5-HT response. A schematic model is proposed to explain our findings and the relationship between this 5-HT receptor and other 5-HT receptor subtypes regulating secretion that have been described in the literature. [ABSTRACT FROM AUTHOR]

The response of a cell line of Xenopus laevis melanophores to serotonin was examined. Serotonin increased intracellular levels of cAMP and induced pigment dispersion in the cells. The responses depended on both the concentration of serotonin applied and on the time for which the cells were exposed to serotonin. Using a recently described, microtiter-plate-based bioassay, a series of serotonin receptor ligands were evaluated as agonists or antagonists at the melanophore serotonin receptor. The pharmacological profile suggests the presence of a receptor which shares some properties with but appears different from other previously described serotonin receptors. [ABSTRACT FROM AUTHOR]

The effects of 5-methoxytryptamine and 5-hydroxytryptamine (5-HT) on both basal and electrically evoked outflow of tritium were studied in guinea-pig myenteric plexus preparations preincubated with [H]-choline. Basal outflow. 5-Methoxytryptamine caused a transient and calcium-dependent increase in basal outflow of [H]acetylcholine that was abolished by tetrodotoxin. Ondansetron (1 μmol/1) did not affect the stimulatory response of 5-methoxytryptamine but ICS 205-930 (1 and 3 μmol/1) produced parallel rightward displacements of the concentration-response curve to 5-methoxytryptamine. The PK value for ICS 205-930 was 6.6 suggesting an involvement of 5-HT receptors. 5-HT caused an increase in basal outflow of [H]acetylcholine and a biphasic concentration-response curve was obtained. The maximal response of the first phase to 5-HT (release of 0.98% of tissue tritium) and the maximal response to 5-methoxytryptamine (0.94% of tissue tritium) were similar but 5-methoxytryptamine (-log EC: 6.9) was less potent than 5-HT (-log EC of the high affinity component: 7.9). ICS 205-930 (0.01-1.0 μmol/1) acted as a competitive antagonist against the low affinity component of the 5-HT concentration-response curve with a pA value of 8.0. It is concluded that stimulation of both 5-HT receptors (by 5-methoxytryptamine and submicromolar concentrations of 5-HT) and 5-HT receptors (by micromolar concentrations of 5-HT) causes a release of acetylcholine which in turn leads to smooth muscle contraction. Electrically evoked outflow. This outflow of [H]acetylcholine was concentration-dependently inhibited by both 5-methoxytryptamine and 5-HT. ICS 205-930 (1 μmol/1) reinforced the inhibitory effect of 5-methoxytryptamine but not that of 5-HT. In the presence of methiothepine (0.1 μmol/1) 5-methoxytryptamine enhanced the evoked outflow of [H]acetylcholine, an effect which was attenuated by 3 μmol/1 ICS 205-930. These results suggest that 5-methoxytryptamine may both inhibit (via 5-HT receptors) and facilitate (via 5-HT receptors) the evoked release of acetylcholine from guinea-pig myenteric neurones. The facilitatory action is unmasked when the 5-HT receptor is blocked by methiothepine. [ABSTRACT FROM AUTHOR]

Agonist-induced desensitization has been utilized to discriminate and independently 'isolate' the neuronal excitatory receptors to 5-hydroxytryptamine (5-HT) in the guinea pig ileum (5-HT and putative 5-HT receptors). Electrically stimulated longitudinal muscle myenteric plexus preparations, and non-stimulated segments of whole ileum were used. Exposure to 5-methoxytryptamine (10 μmol/l) inhibited completely responses to 5-HT at the putative 5-HT receptor without affecting 5-HT-mediated responses. Conversely, exposure to 2-methyl-5-HT (10 μmol/l) inhibited completely responses to 5-HT at the 5-HT receptor without affecting putative 5-HT-mediated responses. The inhibition with 5-methoxytryptamine and 2-methyl-5-HT, either alone or in combination, appeared selective as responses to KCI, DMPP, carbachol, histamine, and substance P were unaffected or only very slightly modified. Furthermore, the pA values for ICS 205-930 at the putative 5-HT (pA = 6.2 to 6.5) and 5-HT (pA = 7.6 to 8.1) receptors (estimated in the presence of 2-methyl-5HT and 5-methoxytryptamine, respectively) were consistent with those estimated in the absence of desensitization. 5-Methoxytryptamine, but not 2-methyl-5-HT, suppressed completely but reversibly the concentration-effect curve to renzapride, suggesting that responses to this agent are mediated exclusively via agonism at the putative 5-HT receptor. It is concluded that 5-methoxytryptamine and 2-methyl-5-HT can be utilized as selective probes to discriminate the putative 5-HT receptor from the 5-HT receptor in guinea pig ileum. This finding is of importance as no selective antagonist exists for the putative 5-HT receptor. Furthermore, the presently described method of agonist-induced desensitization and 5-HT receptor discrimination may be useful for the identification and characterization of the putative 5-HT receptor in other tissues and species. [ABSTRACT FROM AUTHOR]

5-Methoxytryptamine (5-MT), 5-methoxytryptophol (5-ML) and melatonin (Mel) were measured in the plasma after 2, 5, and 8 weeks administration of 25 Μg 5-MT to golden hamsters kept under long photoperiod. 5-MT showed a one compartment kinetic profile in the plasma with half lives of 14.8 min after 2 weeks, 15 min after 5 weeks and 19.1 min after 8 weeks. A rapid metabolism of 5-MT was shown, Mel and 5-ML being detected in the plasma following 5-MT administration. However it was also shown that the gonadal atrophy observed after 5-MT administration cannot be due to its metabolism into these 2 compounds. Indeed when exogenously administered at a dose generating the same plasma concentration as that observed after 5-MT, the gonadal regression observed after the association of 5-ML and Mel is much less than that observed after 5-MT. 5-MT is thus a compound of great physiological interest. [ABSTRACT FROM AUTHOR]

This study tested the photo-dependency of the rhythmic synthesis of 5-methoxytryptamine (5-MT) in the pineal gland of golden hamsters. After pargyline administration, pineal 5-methoxytryptamine and melatonin were measured by HPLC in male golden hamsters kept under short and long photoperiod. In both photoperiodic regimes, a clear 5-MT rhythm was observed which fitted a sinusoidal function with high values occuring during the day-time and low values occuring during the night-time. The duration of the low nighttime levels was clearly proportional to the length of the dark phase. A marked rhythm of melatonin synthesis was also seen with low daytime levels and high night-time values. An inverse relationship between 5-MT and melatonin levels was observed. Thus, after pargyline administration, the rhythms of 5-MT and melatonin in the pineal gland of golden hamsters are photoperiod-dependent and show a reciprocal relationship. [ABSTRACT FROM AUTHOR]

In the European hamster (Cricetus cricetus, L.) pinealectomy as well as a constant high level of either circulating melatonin or 5-methoxytryptamine induce marked changes in the immunocytochemically demonstrable central vasopressinergic innervation. When compared to control animals, a drastic decrease of AVP-immunoreaction was observed in the diagonal band of Broca, the lateral septum, the medial amygdala and the ventral hypothalamus. The results obtained suggest that part of the central vasopressinergic innervation is involved in pineal dependent seasonal functioning of the animal. [ABSTRACT FROM AUTHOR]

Subcutaneous implantation of 5-methoxytryptamine-filled silastic capsules overcomes, in natural as well as in experimental conditions, the inhibitory effect of short photoperiod on the gonadal axis. The results obtained are similar to those obtained after pinealectomy. They indicate that 5-methoxytryptamine when constantly available presents, like melatonin, a progonadal (or counter-antigonadal) effect. Evidently, 5-methoxytryptamine, like melatonin, is involved in the control of the reproductive function. [ABSTRACT FROM AUTHOR]

Late-afternoon-administered 5-methoxytryptamine (5-MT) induces gonadal atrophy in male hamsters kept under long photoperiods (14 hL/ 10 hD). Morning-injection of 1mg 5-MT does not show antigonadal effects. However, 1 mg melatonin (MEL) administered in the morning completely prevents the antigonadotropic effect of 5-MT administered in the late afternoon. This result is specific of MEL since morning injections of 1mg 5-MT do not present this counterantigonadotropic property. When interpreted according to Reiter's concept of down-regulation of MEL receptors, these results suggest that the physiological effects of 5-MT are indirectly due to MEL. [ABSTRACT FROM AUTHOR]

Daily (6 days on 7) subcutaneous injections of 25 μg of 5-methoxytryptamine in saline 0.9% into intact male hamsters given between 9.00 and 9.30 (lights on from 8.00 to 18.00; 10hL/14 hD) during 8 weeks block short photoperiodically induced testicular atrophy. Under these experimental conditions, however, this blockage is not total since the weight of the testes and of the accessory sex organs of the pinealectomized hamsters is higher than that of treated animals. The results indicate that 5-MT, like melatonin, is a physiologically active compound implicated in the control of the reproductive function. [ABSTRACT FROM AUTHOR]

The bioluminescent dinoflagellate Gonyaulax polyedra contains various indoleamines, in particular, melatonin and 5-methoxytryptamine, as well as enzymes of their biosynthetic pathway. Melatonin exhibits a high-amplitude circadian rhythm characterized by a dramatic increase shortly after the onset of darkness. The maximum of melatonin is followed by a peak of 5-methoxytryptamine. These 5-methoxylated indoleamines seem to be involved in the mediation of the information 'darkness'. G. polyedra shows a short-day response, which consists in the formation of asexual cysts. Light break experiments demonstrate the photoperiodic nature of this reaction. Cells become sensitive to short days only upon exposure to a lowered temperature (<16°C). Melatonin mimics the short-day effect, but only at decreased temperature. 5-Methoxytryptamine is even a better inducer of cyst formation, acting also at 20°C and in any lighting schedule, including LL. Cyst induction is associated with stimulation of bioluminescence and cytoplasmic acidification. A model on the intracellular pathway of photoperiodic information transduction assumes increased deacetylation of melatonin under cyst-inducing conditions, binding of 5-methoxytryptamine to the membrane of an acidic vacuole, proton transfer to the cytoplasm, and decreased intracellular pH as the stimulus for encystment. Melatonin shows the property of a scavenger of superoxide anions. This reaction, which is efficiently catalyzed by hemin, leads to the formation of a substituted kynuramine (AFMK). Destruction of melatonin by light-induced superoxide anions in the presence of cellular hemin may represent a property which, during evolution, has made this molecule suitable as an indicator of darkness. On the other hand, AFMK, which is formed under illumination, might have become a mediator of the information 'light'. Photoperiodism in Gonyaulax shows surprising parallels to that in mammals, but allows the analysis of this phenomenon at an entirely cellular level. [ABSTRACT FROM AUTHOR]

5-Methoxytryptamine (5-MT) is taken up rapidly by rat tissues after IP injection (50 mg/kg) and the following peak levels ( μg/g or ml of sample) were observed after 5 min: plasma, 5.3; liver, 126; skeletal muscle, 2.4; brain 0.43. Over 90% of the compound disappeared from the plasma and the tissues studied within 60 min. The compound impaired rope climbing performance of trained rats. Pretreatment of the animals with iproniazid enhanced the effect of 5-MT whereas its main (and probably only) metabolite, 5-methoxyindoleacetic acid, did not interfere with rope climbing at a dose of 75 mg/kg. 5-MT also produced marked cutaneous vasodilatation, analgesia and hindleg paralysis. All pharmacological effects lasted approximately 75 min. It is suggested that 5-MT is the pharmacological active agent and that behavioral changes observed after IP injection of the compound are mainly caused by the peripheral and little, if any, by a central action of this compound. [ABSTRACT FROM AUTHOR]

Encystment, which at a temperature of 15°C is photoperiodically controlled in Gonyaulax polyedra, can also be induced by a decrease of temperature, from 20 to 10 or 8°C in the absence of photoperiodic signals. The cyst-inducing capacity of the decrease in temperature depends on the circadian phase: in constant light, the maximum of sensitivity was found at the beginning of subjective night. In a light/dark cycle, however, cyst formation was reduced during dark phase, indicating that light is required for the process of encystment. A similar light dependence was seen in the effect of the physiologically occurring cyst inducer 5-methoxytryptamine, but not in the encystment response to the protonophores monensin and nigericin. [ABSTRACT FROM AUTHOR]

The article presents the study on the reactivity of ethyl 2-R-4-(2-dimethylaminovinyl)pyrimidine-5-carboxylates with primary amines [1, 2]. The study unexpectedly found the presence of 2-R-10-methoxy-8,13,13b,14-tetrahydroindolo-[2,3-a]pyrimido-[5,4-g]quinolizin-5(7H)-ones rather than the expected pyridopyrimidinones. Presence of tetrahydroquinolizinone rings were recorded on spectrometer and elemental analysis was carried which determined the melting points on a Koffler block.

Pretreatment with the MAO-inhibitors iproniazid, clorgyline, or deprenyl abolishes the effects of LSD on the conditioned avoidance response (CAR) in rats. The effects of serotonin (5-HT) and 5-methoxytryptamine (5-MT) are greatly potentiated by these substances. Brain levels of LSD are not affected by MAO inhibition whereas levels of 5-HT and 5-MT are significantly elevated. It is postulated that the decreased behavioral response to LSD is the result of 'MAO inhibitor-induced' changes whereas the increased response of 5-HT and 5-MT results from increased brain levels of these compounds. [ABSTRACT FROM AUTHOR]