Tryptophan hydroxylase (TPH, the rate-limiting enzyme of serotonin synthesis) protein and mRNA levels display a circadian expression in the rat dorsal and median Raphe. These patterns suggest a rhythmic synthesis of serotonin under the control of the master clock of suprachiasmatic nuclei. In the present study, we examined the involvement of endocrine and behavioral output signals of the master clock upon the TPH2-mRNA levels by quantitative in situ hybridization.

In the absence of adrenals, a complete suppression of TPH2-mRNA rhythm was observed in dorsal and median Raphe over 24h. The restoration of corticosterone daily variations in adrenalectomized rats induced a TPH2-mRNA rhythmic pattern de novo, indicating that TPH2-mRNA rhythm is dependent upon daily fluctuations of glucocorticoids. Enhanced voluntary locomotor activity during 6 weeks increased the level of TPH2-mRNA in both Raphe nuclei of control rats without concomitant increase of corticosterone plasma levels. Moreover, this long-term enhanced locomotor activity was able to restore significant variation of TPH2-mRNA in adrenalectomized rats.

In conclusion, both endocrine and behavioral cues can modulate tph2 expression in dorsal and median Raphe. Corticosterone surge acts as a rhythmic cue that induces the rhythmic expression of tph2 in the Raphe neurons. On the other hand, long-term exercise modulates the expression levels of this gene. Thus, the 5-HT neurons are a target for both endocrine and behavioral circadian cues and the 5-HT input to the SCN might feedback and influence the functioning of the clock itself.