Discussion

This study shows that in adult Syrian hamster SCN 2-iodo-melatonin binding undergoes a dramatic loss within the first 2 months of life, as at PN 60 the melatonin

0 8 Days

Figure 2. Post natal development of the specific 2-iodo-melatonin binding and the specific hybridization of an antisense mt1 cRNA riboprobe in the PT and the SCN of Syrian hamster between PN 0 and PN 8. All values are expressed in percentage by comparison to the PN 0 Value (100%). Each time point is the mean ± SEM of 5 animals.

Figure 3. Post natal development of both the specific 2-iodo-melatonin binding (and the specific hybridization of an antisense mt, cRNA riboprobe in both the PT (A) and the SCN (B) between PN 8 and PN 60 (adulthood). Values are expressed in percentage by comparison to PN 8 value (100%). Each time point is the mean ± SEM of 5 animals.

Figure 3. Post natal development of both the specific 2-iodo-melatonin binding (and the specific hybridization of an antisense mt, cRNA riboprobe in both the PT (A) and the SCN (B) between PN 8 and PN 60 (adulthood). Values are expressed in percentage by comparison to PN 8 value (100%). Each time point is the mean ± SEM of 5 animals.

receptor density is only 7.7% of the PN 0 value. We used a newly subcloned mti Syrian hamster cDNA to investigate the postnatal developmental expression of the mti mRNA within the SCN and the PT of the Syrian hamster to test whether a postnatal regulation of the expression of the mt1 mRNA could generate the observed decline in SCN melatonin receptor density. At a first glance what one could have expected is a dramatic slow-down of mt1 mRNA expression preceding and then leading to low binding capacities in adulthood. Actually, the mechanisms underlying this binding drop appear to be more complicated. Indeed, when considering the PT as a control, postnatal variations of both specific 2-iodo-melatonin binding and mti mRNA expression are highly correlated (r = 0.98, P < 0.003) from PN 8 to PN 60. This strongly suggests that the observed postnatal variations of PT melatonin receptor density are, in the PT, a direct consequence of the postnatal mti mRNA expression variations.

This conclusion can also be proposed to explain the initial drop of the SCN mela-tonin binding capacity between PN 0 and PN 8, as during this first step the binding capacity decline correlates with mRNA expression slow-down. However after PN 8, in contrast to what was observed in the PT, the melatonin receptor density dramatically followed its drop in the SCN while the mRNA expression level got stabilized at 40%

of the PN 0 value. Therefore, the dramatic post natal loss of melatonin receptor in the SCN can not be attributed to an inhibition of the mRNA expression, but certainly to a post transcriptional blockade of the mti receptor expression.

This study provides the first evidence of a regulation of the melatonin receptor involving both transcriptional (before PN 8) and post-transcriptional (after PN 8) mechanisms that may directly influence a key role of melatonin: its feed-back effect on SCN circadian functions. In free running rodents, like the rat or the mouse, which present a robust melatonin receptor density, the locomotor activity rhythm is either phase shifted or entrained by melatonin injections. Furthermore, experiments showing a direct melatonin resetting activity of rat SCN electrical activity in vitro clearly support the hypothesis that this exogenous melatonin directly acts on the rat SCN through melatonin receptors (see 1,2,3,11,22). According to this model, the dramatic decline in SCN melatonin receptor density observed in the Syrian hamster should obviously affect the ability of the SCN to read the melatonin humoral message and therefore would explain the absence of melatonin specific effect of melatonin injections on the locomotor activity of free-running hamsters (8,9). Our results thus strongly suggest that a post transcriptional blockade of the expression of the mt1 melatonin receptor in the SCN would take place after PN 8 and consequently would induce a dramatic loss of SCN melatonin receptors that might be responsible for the SCN non response to acute melatonin injections.

These results however do not necessarily imply that Syrian hamster circadian functions should be totally unresponsive to both exogenous and endogenous melatonin on a long term basis. Indeed, exogenous melatonin administered by infusion during long periods of time has been reported to entrain pinealectomized Syrian hamsters locomotor activity [Schuler et al., this issue]. Therefore, the understanding of the neuronal circuitry involved in the regulation of biological circadian rhythms like the locomotor activity requires more than ever fundamental investigations into the physiological role of the melatonin secretion in terms of daily and seasonal functions.

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