Pura J. Requintina

Stimulation of rat pineal melatonin biosynthesis by N-acetylserotonin.

Rat pineal content of melatonin and related indoles (HPLC-fluorimetric procedure) was evaluated after injections of N-acetylserotonin, the immediate precursor of melatonin. The increase of melatonin and NAS but of no other indoles was observed after daytime (but not after nighttime) NAS administration. NAS-induced stimulation of melatonin biosynthesis was dose- and time-dependent. Maximum pineal melatonin levels after NAS injections were similar to physiological night time peak of melatonin levels. It is suggested that NAS-induced stimulation of pineal melatonin biosynthesis might be used as the physiological way of pineal gland stimulation for diagnostic and therapeutic purposes.

The response of the pineal melatonin miosynthesis to the selective MAO-A inhibitor, clorgyline, in young and middle-aged rats

1. Clorgyline increased pineal melatonin and N-acetylserotonin (NAS) and decreased 5-hydroxyindoleacetic acid (5-HIAA) content in 3 and 12 months of age male Sprague-Dawley rats kept under 12:12 h light: dark schedule. Exposure to light for 24 h before clorgyline administration resulted in additional elevation of NAS and melatonin. NAS and melatonin levels after clorgyline injections were significantly higher while 5-HIAA levels were significantly lower in young than in middle-aged rats. 2. The 5-HIAA/5-HT ratio (index of monoamine oxidase activity) was higher in middle-aged than in young rats suggesting the lesser degree of clorgyline-induced inhibition of MAO-A in old than in young rats. 3. It is suggested that melatonin response to a single dose of the selective MAO-A inhibitor might be used for the assessment of the aging changes of the rat (and human) pineals.

The effect of 6-months l-deprenyl administration on pineal MAO-A and MAO-B activity and on the content of melatonin and related indoles in aged female Fisher 344N rats

Six months of administration of the selective MAO-B inhibitor, selegiline (l-deprenyl 0.25 mg/kg, s.c.) to aged female Fisher 344N rats suppressed MAO-A as well as MAO-B activity and increased serotonin (substrate for melatonin biosynthesis) and N-acetylserotonin (immediate melatonin precursor) levels in pineal glands taken from the animals during the night. Daytime values were unchanged by the treatment. The data suggest that stimulation of pineal melatonin biosynthesis might be one of the consequences of MAO-A inhibition contributing to life span prolongation induced by chronic selegiline treatment.

Synergistic sedative effect of selective MAO-A, but not MAO-B, inhibitors and melatonin in frogs

Total suppression of righting reflex in frogs (Rana pipiens, 25-35 mg b.w.) was observed after combined administration of melatonin (12.5 mg/kg) and selective inhibitors of MAO-A: clorgyline (2.5 mg/kg) and moclobemide (50 mg/kg) but not MAO-B: selegiline (25 mg/kg) and Ro-19-6327 (50 mg/kg). None of these drugs alone affected the righting reflex. Clorgyline and selegiline selectively inhibited brain MAO-A and MAO-B activity (by more than 90%), resp. Frogs might represent a convenient model to study the selective MAO-A and B type inhibitors since they provide the opportunity to correlate behaviour and biochemical changes induced by MAO inhibitors.

Chronic effect of the irreversible and reversible selective MAO-A inhibitors on rat pineal melatonin biosynthesis

Acute administration of the irreversible MAO-A inhibitor, clorgyline (2.0 mg/kg, s.c.) and the reversible MAO-A inhibitor, moclobemide (10 mg/kg, s.c.), increased rat pineal melatonin and related indoles content (HPLC-fluorimetric method). Chronic (21 days) administration of clorgyline attenuated the acute effect of clorgyline on pineal melatonin biosynthesis. The acute effect of moclobemide on melatonin biosynthesis was not affected by chronic moclobemide administration. The observed difference in the chronic effects of irreversible and reversible selective MAO-A inhibitors on melatonin biosynthesis could have clinical implications.

Chronopharmacological study of moclobemide effect on the rat pineal melatonin biosynthesis

The chronopharmacological hypothesis of the mechanism of the antidepressant effect of MAO-A inhibitors predicts that clinical efficacy depends upon the time of the day at which the drugs are administered. In the present study moclobemide (10 mg/kg, s.c.) injected at the end of the light phase advanced the onset of the nighttime increase of the rat pineal melatonin biosynthesis while the same dose of drug injected at the end of the dark phase delayed the daytime decrease of melatonin biosynthesis. The results obtained suggest that the timing of MAO-A inhibitor administration should be considered in clinical practice.

Clorgyline effect on pineal melatonin biosynthesis in roman high- and low-avoidance rats

Pineal melatonin and related indoles levels were higher in Roman high- than in Roman low-avoidance rats, while 5-HIAA/5-HT ratio, as an index of MAO activity was higher in low- than in high-avoidance rats. Clorgyline stimulated pineal melatonin biosynthesis in both lines of rats. However, melatonin and N-acetylserotonin levels remained higher and 5-HIAA levels remained lower in the high avoidance rats treated with low dose (0.5 mg/kg) while treatment with 1.0 mg/kg of clorgyline eliminated the differences in melatonin production between high- and low-avoidance rats.