Acute low doses of melatonin stimulate rat sex behavior: the role of serotonin neurotransmission

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Abstract

Melatonin is known to inhibit male and female sex behavior, but this effect has been reported only after repeated administration of sustained doses of the hormone. The present experiments were performed in order to study the effects of acute treatment with low doses of melatonin on rat male and female sex behavior in a dose–response paradigm. After four mating tests with a receptive female, sexually active male rats of the Wistar strain were injected intraperitoneally (i.p.) with small doses of melatonin (10, 50 and 100 μg/kg) administered acutely 1 h before a 30-min mating test. Melatonin (50 and 100 ng/2 μl) or its analogs, 6-chloromelatonin (2 and 4 ng/2 μl) and 2-iodomelatonin (5 and 10 ng/2 μl) were also injected intracerebroventricularly (i.c.v.) 30 min before mating. Either treatments caused a reduction of the latency to the first mount, intromission and ejaculation. An increase in the frequency of mounts, intromissions and ejaculations was also observed. Inhibition of sexual activity was observed when a greater dose (1 mg/kg) of melatonin was repeatedly injected for 14 days. Female sex behavior, measured by the lordosis quotient in Wistar female rats, was not affected by acute treatment with the hormone, while it appeared to be inhibited by the repeated injection. The facilitating effect of acute i.p. or i.c.v. melatonin low doses on sexual activity of male rats was partially abolished by the pre-treatment with the non-selective melatonin antagonist, luzindole (0.25 mg/kg, injected subcutaneously), and totally suppressed by the injection of small quantities of serotonin or the 5H2A–5H2C receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane into the amygdala. These results suggest that melatonin may exert opposite effects on male and female sex behavior depending on the dose and duration of treatment.

Introduction

The vertebrate pineal gland rhythmically produces melatonin, a hormone involved in the regulation of several physiological and behavioral processes. The rate-limiting step in melatonin production is the N-acetylation of serotonin by arylalkylamine N-acetyltransferase (Coon et al., 1995) The activity of this enzyme seems to be under control of the suprachiasmatic nucleus (SCN) in the hypothalamus, that receives neural afference from the retina indicating daily light/dark alternance. Thus, SCN regulates melatonin synthesis in relation of environmental light. As a result, high levels of melatonin are produced in vertebrates during the dark part of the daily light–dark cycle.

The physiological and pharmacological effects of melatonin seem to be mediated by activation of high-affinity receptors, but may involve different neurotransmitters in the brain Gaffori and Van Ree, 1985a, Tenn and Niles, 1995. In particular, serotonin has been often considered as a possible mediator of melatonin effects Gaffori and Van Ree, 1985b, Eison et al., 1995. The main action of the hormone deals with adaptation of animal behavior, including sex behavior, to the length of the dark period of the circadian cycle, hence, to the seasons. Similar effects may be mimicked through the exogenous administration of melatonin. Animal studies show, for instance, that its chronic administration leads to inhibition of male sex behavior Baum, 1968, Yamada et al., 1992 and the implantation of melatonin-containing pellets near the SCN in female rats reduces their lordosis reflex (De Catanzaro and Stein, 1984). Besides, melatonin is involved in sexual cycle of the female rat. In particular, it was observed that melatonin administered by intraperitoneal (i.p.) injection produces an inhibiting effect on the nervous structures involved in the regulation of sexual cycle of female rats (Diaz Lopez and Fernandez, 1984). All these experiments, however, were made using rather high doses of melatonin. Furthermore, to date no report is available on the effect of melatonin on male or female rat sex behavior after acute administration.

Purpose of the present study was to determine the influence of acute treatments with melatonin on rat male and female sex behavior in a dose–response paradigm. Drug doses were selected in a range rather lower than that used in previous experiments, and closer to physiological blood concentration of melatonin. Although the sexual effects of melatonin have been studied in a wide range of animal species Bittman and Karsch, 1984, Lincoln and Ebling, 1985, Pitrosky et al., 1991, Mendonca et al., 1996, the rat was selected as the most studied species for behavioral experiments.

Section snippets

Animals and surgery

Male rats of the Wistar strain (purchased from Charles River, Italy) weighing 350±25 g were used throughout all experiments. A group of female rats of the same strain, weighing 150±10 g was also used. Animals were kept three or four to a cage, at a constant temperature of 21°C, with food and water available ad libitum. At least, 1 week before the beginning of the experiments, they were housed under a reversed light–dark cycle (light on between 0300 and 1500 h). A group of male rats were

Effects on male sex behavior

Acute i.p. injection of melatonin in sexually active male rats reduced the latency to the first mount, intromission and ejaculation and increased the frequency of mounts, intromissions and ejaculations (Table 1). This effect, however, did not appear to be dose-dependent. Similar results were observed after i.c.v. injection of melatonin and its analogs, 6-chloromelatonin and 2-iodomelatonin (as shown in Fig. 1A and B, where only ejaculation parameters are presented). Again, a reduced latency to

Discussion

The physiology of reproduction in mammals seems to be under control of melatonin Meyer and Theron, 1988, Tijmes et al., 1996. This hormone also exerts a profound influence on sex behavior. Chronic administration of melatonin leads to the inhibition of male sexual activity (Yamada et al., 1992). The implantation of a melatonin-containing beeswax pellet near the SCN in female rats reduced their lordosis reflex when exposed to the males (De Catanzaro and Stein, 1984). Besides, i.p. injection of

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