Discussion

These results show that the expression of mt1 melatonin receptor mRNA is rhythmic in L/D and in D/D conditions, with a quite similar 24 h time course pattern in both conditions. The daily variations in mt1 melatonin receptor expression are thus circadian in the rat PT.

Figure 1. Diurnal variations in mt1 mRNA levels (O) and in 2-i2sI-melatonin specific binding (•) in the pars tuberalis of rats kept in a 12h light/12h dark regime (lights on at 07.00 h). Each point represents the mean ± SEM of five animals.

In a previous study, we showed in this species the presence of an endogenous rhythm in the density of PT melatonin receptors, which was not driven by the external light/dark cycle (3). The present results confirm and extend these findings. We show here that the 2-125I-melatonin binding increase at the light/dark transition or at the late subjective night in L/D and D/D, respectively, follows by approximately 5 hours a parallel increase in mti mRNA expression. At a first glance, it could indicate that the melatonin receptor density might correlate, with a phase delay, to the mti mRNA synthesis. However, the significance of this time lag must be carefully analyzed since

Figure 2. Circadian variations in mti mRNA levels (O) and in 2- I-melatonin specific binding (®)in the pars tuberalis of rats placed for three days in continuous darkness. Each point represents the mean ± SEM of five animals.

many different factors could be interfering. For example, since the mRNA levels, as well as the protein levels, are depending on the balance between synthesis and degradation, it would be necessary to consider the turnover rates of both the mRNA and the protein. Moreover, it was described in the ovine PT in vitro, that forskolin which induces an important stimulation of the mti mRNA levels, affects only moderately the melatonin receptor density (1). For these authors posttranscriptional mechanisms could exist which would regulate the receptor protein translation. Then, although our results demonstrate the circadian rhythmicity of the mt1 mRNA in the rat PT, the physiological significance of this fluctuation on the receptor protein remains to be investigated.

A second arising question concerns the role of the nocturnal melatonin peak in the regulation of the mt, mRNA transcription. The mt1 mRNA levels in L/D and D/D conditions starts to increase during the night, at about the same time when the nocturnal plasma melatonin peak starts to decrease. This observation could suggest that a decrease in plasma melatonin concentration could remove an inhibition of the mt1 receptor transcription. There is some evidence that melatonin could inhibit the mti mRNA expression in the ovine PT. Indeed, Barrett and colleagues (1), showed that melatonin suppresses partially the spontaneous increase in mti gene expression and reverses the stimulatory effect of forskolin induced increase in mt1 mRNA levels in cultured cells of sheep PT. Thus, it seems possible that melatonin could regulate negatively the synthesis of mti mRNA and thus indirectly the synthesis of mti receptors. Measurement of mti mRNA throughout the L/D cycle after suppression of the melatonin peak, e.g., after pinealectomy, will allow us to answer this question. Nevertheless, the possibility of a direct effect of melatonin on the regulation of the receptor protein must not be underestimated.

In conclusion, this study provides the first evidence of a circadian regulation of the mti mRNA subtype in the pars tuberalis in vivo. Further studies are in progress to provide more clues about the physiological mechanism of melatonin receptors.

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