Evidence for a Regulatory Role of Melatonin on Serotonin Release and Uptake in the Pineal Gland

Abstract

Melatonin has been proposed to exert some regulatory actions within the pineal gland itself. The present study examined the effect of melatonin on the release of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) from rat pineal glands by using an in vitro perifusion system. Melatonin induced a concentration-dependent stimulatory effect on 5-HT secretion from 10(-6) M to 10(-3) M. Maximal effects were obtained with melatonin 10(-3) M and concentrations lower than 10(-6) M were without effect. The secretion of 5-HIAA was inhibited by melatonin 10(-3) and 10(-4) M, but it was increased when pineals were incubated with 10(-5) and 10(-6) M of melatonin. The indoleamine secretion was also studied on peripherally denervated rat pineal glands. Basal output of 5-HT from these glands was increased when compared with those from control rats. In contrast, the secretion of 5-HIAA was strongly reduced after removal of the sympathetic input to the pineal gland. Melatonin 10(-3) M failed to stimulate 5-HT release from denervated pineal glands, although it inhibited 5-HIAA secretion. In contrast, melatonin 10(-5) M enhanced 5-HT release without altering 5-HIAA output. Fluoxetine, a 5-HT uptake inhibitor, produced similar effects than mM concentrations of melatonin on the indoleamine secretion from control pineal glands, but it had no effect on glands taken from peripherally denervated rats. These data suggest that mM concentrations of the pineal hormone are able to stimulate 5-HT release from the pinealocyte, while mM concentrations of melatonin increase extracellular 5-HT by inhibiting its reuptake in the adrenergic nerve endings. These findings are discussed in relation to the possible role of melatonin regulating the intra- and extracellular availability of 5-HT in the pineal gland and its significance as an autocrine factor.

Pilot Investigation of the Circadian Plasma Melatonin Rhythm across the Menstrual Cycle in a Small Group of Women with Premenstrual Dysphoric Disorder

“…Melatonin is synthesized in the pineal gland from the precursor serotonin [44], and is secreted in a circadian manner via inputs from the SCN. Melatonin seems to have a regulatory role on serotonin, as melatonin caused increased serotonin release from rat pineal glands in vitro [45], and pinealectomy in rats caused significant reductions in serotonin within the hypothalamus, midbrain and hippocampus [46]. Several anti-depressant drugs induce increased melatonin secretion, as illustrated by significant increases in plasma melatonin [47] and urinary 6-sulfatoxymelatonin [48] in depressed patients after treatment with a tricyclic antidepressant and MAO inhibitor, respectively.…”

The chronobiotic properties of melatonin

“…The possibility that such high levels can pharmacologically influence other types of receptors or neurotransmitters within the SCN clock has to be considered because it would provide a mechanism by which Mel can have a parallel effect on SCN activity. Supraphysiological levels of Mel are known to inhibit 5-hydroxytryptamine (5-HT) reuptake in rat nerve endings (Cardinali et al 1975;Miguez et al 1995). Administration of serotonin receptor agonists in vivo also phase-shift rodent circadian clock.…”

Generation of the Melatonin Endocrine Message in Mammals: A Review of the Complex Regulation of Melatonin Synthesis by Norepinephrine, Peptides, and Other Pineal Transmitters

“…For example, in neonate but not adult rats, the pineal gland displays MEL-R binding (Zitouni et al, 1995). Exogenous MEL modifies various morphological and biochemical pineal parameters, namely proteic microtubules , enzymatic activities , presynaptic release of neurotransmitters , and pre and postsynaptic release of the MEL precursor serotonin (5-HT; Miguez et al, 1995b).…”