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S.c. injection of 25 microgram of methoxytryptamine (5-MT) in oil into adult male hamsters given between 4.30 and 5 p.m. (light on from 5 a.m. to 7 p.m.: 14 L/10 D) for 51 consecutive days caused involution of the testes. Similar injections of 5-MT given between 8.30 and 9.30 a.m. completely failed to cause regression of the gonads. Under the same conditions, 5-methoxytryptophan (5-MTP) did not induce gonadal atrophy, neither in the morning nor in the late afternoon. These results indicate that, like malatonin, 5-methoxytryptamine is implicated in the control of the reproductive function.

In the pineal of 21-day old male Wistar rats hydroxyindole-O-methyl-transferase (HIOMT) activities involved in the synthesis of several 5-methoxyindoles were determined during the night in April, June, October and January. A high HIOMT activity for the synthesis of melatonin/5-methoxytryptophol was determined in the months of January and April. In June and October a decrease was observed. The activity maxima coincide with peaks of activity found for the synthesis of 5-methoxytryptophan. Synthesis of 5-methoxytryptamine occurred only in June and October, whereas the synthesis of 5-methoxyindole-3-acetic acid occurred only in January. From these results it may be concluded that January and April are the most active months of those tested for the melatonin/5-methoxytryptophol synthesis in the rat pineal gland. A possible physiological role of the 5-methoxyindoles other than melatonin and 5-methoxytryptophol is discussed.

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.

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.

Hydroxyindole-O-methyl transferase activity for the synthesis of 5-methoxyindoles was investigated in the pineal gland of 28 day old male Wistar rats after exposure to white, red and green light for 12 hours daily. It could be demonstrated that, in comparison to white light, red light causes a shift of HIOMT activity for the synthesis of melatonin/5-methoxytryptophol towards an earlier period being highest between 12 and 16 hours. The synthesis of 5-methoxytryptamine and of 5-methoxytryptophan is shifted to 16 hours, while the synthesis of 5-methoxyindole-3-acetic acid, which normally peaks at 16 hours, is increased at this same hour. Green light shifts HIOMT activity for the synthesis of melatonin/5-method being highest between 12 and 16 hours. The synthesis of 5-methoxytryptamine and of 5-methoxytryptophan is shifted to 16 hours, while the synthesis of 5-methoxyindole-3-acetic acid, which normally peaks at 16 hours, is increased at this same hour. Green light shifts HIOMT activity for the synthesis of melatonin/5-method being highest between 12 and 16 hours. The synthesis of 5-methoxytryptamine and of 5-methoxytryptophan is shifted to 16 hours, while the synthesis of 5-methoxyindole-3-acetic acid, which normally peaks at 16 hours, is increased at this same hour. Green light shifts HIOMT activity for the synthesis of melatonin/5-methoxytryptophol to a later period, showing a peak at 24 hours. The synthesis of 5-methoxytryptamine is significantly increased at 24 hours. An increase is also observed in the synthesis of 5-methoxyindole-3-acetic acid at 12 and at 4 hours, times at which this synthesis is also maximal using white light, whereas the synthesis of 5-methoxytryptophan is generally decreased. A possible relationship between the present results and those obtained after exposure to different wavelengths of light on N-acetyltransferase activity, the effect of pterins on HIOMT activity and the effect of different wavelengths on gonadal growth are discussed.

In the European hamster (Cricetus cricetus,L.) pinealectomy as well as a constant high level of either circulating melatonin or 5-methoxytryptamine induced 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.

Subcutaneous injections fo 25 micrograms of 5-methoxytryptamine (5-MT) in oil into intact and pinealectomized male hamsters given between 4.30 p.m. and 5 p.m. (light on from 5 a.m. to 7 p.m.; 14 L/10 D) for 54 consecutive days caused involution of the testes. 5-MT, however, is more effective when the pineal is present. These results indicate that melatonin is not the only pineal factor inducing gonadal atrophy in the hamster. 5-MT seems even more effective than melatonin in so far as it is, contrary to melatonin under the same experimental conditions, also effective in the absence of the pineal. Like melatonin, 5-MT appears to be implicated in the control of the reproductive function.

Until now the day/night and seasonal rhythmicity in the synthesis of 5-methoxyindoles (MI) is thought to be regulated by environmental factors, especially photoperiod and temperature. Endogenous factors are also implicated in the generation of N-acetyltransferase and hydroxyindole-O-methyltransferase activity rhythms. In the present experiments seasonal rhythmicity in the synthesis of MI in the pineal gland was investigated in hamsters kept under the same artificial conditions throughout the year. Though the environmental conditions were the same, day/night and seasonal rhythmicity in the production of MI in the pineal were observed indicating the existence of endogenous factors influencing the rhythmicities. In November, most of the MI showed the highest synthesis, MA and ML excepted, which were especially produced in July and September. The results obtained sustain the hypothesis that aMT is synthesized from MT rather than from aHT. Moreover, the rhythmicities in aMT synthesis are not identical to those found in aMT concentration as described in the literature. This indicates that synthesis and concentration of a compound are not comparable. At the end of the light period, when aMT injections have an antigonadotropic effect, a peak of aMT synthesis was always present. Although MI synthesis showed seasonal rhythmicity, no reproductive cycle occurred in the hamsters. At present, the concept that the pro- and/or antigonadal effects of the pineal are mediated by aMT seems to be the most acceptable. The present results, however, indicate that aMT and perhaps other MI, often regarded as factors influencing gonadal growth in golden hamsters, are not the only factors involved.

In frogs with the epileptogenic foci made by injection of penicilline (1000 U in 0.4 mcl) in the primordial hippocampus it was shown that preliminary administration of two kynurenines quinolinic acid (0,1 microgram) and d,l-kynurenine (1 microgram), in the foci region, and their injection in the functioning epileptogenic foci led to a strong increase of the interictal epileptiform discharges and of the electrographic correlates of fits on the EEG. Anthranilic acid (0.1, 1.0 and 5.0 micrograms) did not influence the activity of epileptogenic foci. Serotonin (1 microgram) and 5-methoxytryptamine (1 microgram) essentially decreased it. Provocating effect of kynurenines on neurons in epileptogenic foci is supposed to play a certain role in pathogenesis of epilepsy.

The pineal gland concentration of the four 5-methoxyindoles: melatonin, 5-methoxytryptamine, 5-methoxytryptophol and 5-methoxyindole-3-acetic acid, were measured by gas chromatography-mass spectrometry. The pineal glands were obtained from 11 subjects 2-3 hours post mortem. The concentration of 5-methoxytryptophol ranged from 4-93 pmoles/g, 5-methoxyindole-3-acetic acid from 79-560 pmoles/g and melatonin from 24-6860 pmoles/g. 5-methoxytryptamine was present only in trace amounts (0-12 pmoles/g). A variation over time of these compounds was not evident from the data obtained.

In the present study, the synthesis of methoxyindoles in the neural part and in the pigment epithelial layer of the retina of the frog eye was investigated on the basis of naturally occurring substrate at regular intervals during a 24 hour period. Melatonin, 5-methoxytryptophol and 5-methoxyindole acetic acid were synthesized by the neural part of the retina only, while 5-methoxytryptamine and 5-methoxytryptophan were produced by both, the neural part of the retina and the pigment epithelium. The synthesis of melatonin and of 5-methoxytryptamine showed a diurnal rhythmicity. The results obtained clearly indicate that another cell type, i.e. pigment cells, is involved in indole metabolism besides photoreceptor elements. A possible functional relationship between different methoxyindoles and different retino-motor processes in the amphibian eye is discussed.

Daily (6 days on 7) subcutaneous injections of 25μg 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.

Testes weight, plasma FSH and LH concentration and pineal methylating capacity were compared in hamsters housed under either long (LD 14∶10) or short (LD 8∶16) photoperiods. Hamsters housed for 14 weeks under short photoperiod showed gonadal atrophy, which was complete after 6 weeks. Also plasma FSH and LH concentration showed a marked decline after transfer to short photoperiod. However, after 14 weeks the concentration of FSH and LH as well as testes weight increased again. Under both photoperiods day/night rhythms in plasma FSH and LH concentration were measured. Under both light regimes the concentrations did not show significant differences. Under long as well as short photoperiods in the pineal gland of animals no significant differences were found in the daily synthesis of various MI tested. Only the synthesis of ML was significantly higher in the pineal of hamsters housed under short photoperiod. The function of this higher synthesis of ML remains unknown. Although the maxima of the rhythm for the various MI found under different LD regimes did not differ in magnitude or duration, their location in respect to the onset of darkness was different. It is suggested that this specific location is of more physiological importance than the quantity or duration of synthesis, concentration or release of MI. At the moment the day/night rhythms were determined there were indications that recrudescence of the testes had already started. It is suggested that this recrudescence is responsible for the fact that no differences in the synthesis of MI were found comparing the influence of both photoperiods. After 14 weeks of exposure to short photoperiod, aML synthesis was, in contrast to the synthesis of the other MI, (not significantly) higher under LD 8∶16. Moreover, opposite results for aMT and aML synthesis during darkness were found. It is suggested that the ratio of synthesis of these compounds is of physiological significance.

Using a method in which no substrate is added to the incubation medium, the capacity of HIOMT to synthesize 5-methoxytryptophan, 5-methoxytryptamine, 5-methoxyindole-3-acetic acid, 5-methoxytryptophol and melatonin has been determined in the pineal and the eyes of the mole, a mammal having an atrophied visual system. The results demonstrate that the indoleamine metabolism in the retina is similar to the indoleamine metabolism in the pineal. Moreover, in all animals studied both eyes together synthesize 2 to 30 times more of 5-methoxyindoles than the pineal, a result which proves again that the pineal is not the only and not always the most important source of 5-methoxyindoles. With the exception of 5-methoxyindole-3-acetic acid, the synthesis of which is practically neglectable, the production of all other 5-methoxyindoles in the pineal as well as in the retinae is always larger than that of melatonin. In the pineal, 5-methoxytryptophan, for example, is synthesized in a quantity which is 60 to 170 times larger than that of melatonin, while in the retinae the synthesized amount of 5-methoxytryptophan is even 60 to 1000 times larger than that of melatonin.