Endogenous Regulation of Serotonin Release in the Hamster Suprachiasmatic Nucleus

Abstract

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.

Midbrain Raphe Modulation of Nonphotic Circadian Clock Resetting and 5-HT Release in the Mammalian Suprachiasmatic Nucleus

“…Electrode output was interfaced with an IBM-compatible computer that recorded and analyzed the data. Authenticity of the 5-HT peak in SCN microdialysate was verified by predictable changes in its size after electrical and pharmacological stimulations of the raphe and localized administration of pharmacological agents to the SCN via the dialysis probe (Dudley et al, 1998).…”

“…Procedures for microdialysis probe construction are similar to those of previous studies (Dudley et al, 1998). Concentrically designed probes were constructed from a 26 gauge stainless steel outer cannula (Small Parts, Miami, FL) into which was inserted a beveled 32 gauge fused silica tube (Polymicro Technologies, Phoenix, AZ).…”

“…The intrinsic pattern of activity of 5-HT neurons varies in accordance with behavioral state (Trulson and Jacobs, 1983;Jacobs and Fornal, 1997), and 5-HT release induced in the SCN by behavioral phase-resetting stimuli (Dudley et al, 1998;Grossman et al, 2000) could serve as an intrinsic clock-resetting feedback signal. Although a role for 5-HT is not certain (Bobrzynska et al, 1996;Mintz et al, 1997;Meyer-Bernstein and Morin, 1998), evidence supporting a phase-resetting action of 5-HT in the SCN includes reports that in vitro application of 5-HT receptor agonists to the SCN brain slice preparation during subjective midday advances the circadian rhythm of neuronal activity (Prosser et al, 1990Medanic and Gillette, 1992;Shibata et al, 1992).…”

“…Notably, behavior-related changes in raphe GABAergic activity could underlie the circadian phaseresetting effects of sleep deprivation . During the day, when SCN 5-HT release is low (Dudley et al, 1998), there is strong GABAergic inhibition of raphe activity associated with the sleep state (discussed above). In the proposed model in Figure 9, sleep deprivation-induced SCN 5-HT release (Grossman et al, 2000) is attributed to a behavior-arousalmediated suppression of DRN GABAergic tone.…”

“…For example, there is evidence that 5-HT acts in the SCN to mediate the clock-resetting effects of behavioral stimulation. This includes findings that 5-HT agonists applied to the SCN in vitro or in vivo reset circadian phase (Prosser et al, 1990Medanic and Gillette, 1992;Challet et al, 1998;Ehlen et al, 2001) and that behavioral phaseresetting manipulations evoke SCN 5-HT release (Dudley et al, 1998;Grossman et al, 2000). Conversely, reports that raphe lesions (Meyer-Bernstein and Morin, 1998), treatment with 5-HT antagonists (Antle et al, 1998), or depletion of 5-HT in the SCN (Bobrzynska et al, 1996) do not block behavioral phase shifting argue against a role of 5-HT in circadian clock resetting.…”