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Serotonin (5-HT) has been strongly implicated in the regulation of the mammalian circadian clock located in the suprachiasmatic nuclei (SCN). However, little is known of the pattern of neuronal 5-HT release in the SCN or of the factors involved in regulating its release. Using in vivo microdialysis, we demonstrated the existence of a daily rhythm in the output of 5-HT in the SCN of freely behaving hamsters. This rhythm was characterized by a sharp increase in release from a nadir during late midday to peak levels at the light/dark transition. Output declined to basal levels throughout the remainder of the night. A similar pattern also was evident under constant darkness, with increased 5-HT output occurring at the onset of subjective night. Locomotor activity induced by exposure to a novel running wheel had a pronounced phase-dependent effect on 5-HT release in the SCN, with stimulation during the light phase and suppression during the late dark phase. Systemic application of the somatodendritic 5-HT1A agonist BMY 7378 had a significantly greater suppressive effect on 5-HT release in the SCN during the late dark phase compared with mid light phase, indicating that a variation in raphe autoreceptor response may underlie the time-dependent effects of wheel running on 5-HT release. Collectively, these results show that the daily rhythm in output of 5-HT in the SCN is generated endogenously, and that behavioral state can strongly influence serotonergic activity in the circadian clock in a phase-dependent manner.

The distribution of neurons in the medullary reticular formation (RF) activated by the ingestion of sucrose or rejection of quinine was examined using standard immunohistochemical techniques to detect the expression of the Fos protein product of the immediate-early gene c-fos. Double-labeling techniques were used to gain further insight into the possible functional significance of RF neurons exhibiting Fos-like immunoreactivity (FLI). Compared with sucrose and unstimulated controls, quinine elicited significantly more FLI neurons in three specific RF subdivisions: parvocellular reticular nucleus (PCRt), intermediate reticular nucleus (IRt), and dorsal medullary reticular nucleus (MdD). Moreover, the number of FLI neurons in the RF of quinine-stimulated animals was significantly correlated with the degree of oromotor activity. Thus, the distinct distribution of FLI neurons throughout the RF after quinine may reflect the activation of a specific oral rejection circuit. The double-labeling results indicated a high degree of segregation between FLI neurons and premotor projection neurons to the hypoglossal nucleus (mXII) retrogradely labeled with Fluorogold. Thus, although there were a significant number of double-labeled neurons in the RF, the major concentration of premotor projection neurons to mXII in IRt were medial to the preponderance of FLI neurons in the PCRt. In contrast, there was substantial overlap between FLI neurons in the RF and labeled fibers after injections of the anterograde tracer, biotinylated dextran into the rostral (gustatory) portion of the nucleus of the solitary tract. These results support a medial (premotor)/lateral (sensory) functional topography of the medullary RF.