In Vivo Assessment of the Midbrain Raphe Nuclear Regulation of Serotonin Release in the Hamster Suprachiasmatic Nucleus

Abstract

Serotonin (5-HT) plays important regulatory roles in mammalian circadian timekeeping; however, little is known concerning the regulation of serotonergic activity in the circadian clock located in the suprachiasmatic nuclei (SCN). By using in vivo microdialysis to measure 5-HT release we demonstrated that electrical or pharmacological stimulations of the dorsal or median raphe nuclei (DRN and MRN, respectively) can alter basal release of 5-HT in the hamster SCN. There were similar increases in SCN 5-HT release after electrical stimulation of either the MRN or DRN, indicating that both could contribute to the serotonergic activity in the SCN. Systemic pretreatment with the 5-HT antagonist metergoline abolished DRN-induced SCN 5-HT release but had little effect on MRN-induced SCN 5-HT release, suggesting different pathways for these nuclei in regulating 5-HT output in the SCN. Microinjections of the 5-HT1A autoreceptor agonist 8-OH-DPAT or antagonist WAY 100635 into the MRN caused significant inhibition and stimulation of SCN 5-HT release, respectively. Both drugs had substantially less effect in the DRN. These differential drug actions indicate that somatodendritic 5-HT1A autoreceptors on MRN neurons provide the prominent raphe autoregulation of 5-HT output in the SCN. Collectively the current results are evidence that DRN as well as MRN neurons can contribute to the regulation of 5-HT release in the hamster SCN. On the basis of the current observations and those from recent anatomic tracing studies of serotonergic projections to SCN it is hypothesized that DRN input to the SCN could be mediated by a DRN --> MRN --> SCN pathway involving a 5-HT-sensitive multisynaptic interaction between the DRN and MRN neurons.

Circadian genes, rhythms and the biology of mood disorders

“…Indeed, serotonin neurons from the midbrain raphe nuclei innervate the SCN, and local applications of 5-HT or 5-HT 1A and 7 receptor agonists to the SCN will also produce a phase advance in circadian activity (Dudley et al, 1999;Ehlen et al, 2001). Thus antidepressants in the selective serotonin reuptake inhibitor (SSRI) class may also exert some of their effects on depression through modulation of the circadian clock.…”

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

“…Nonspecific excitation by passive current spread from the DRN to the MRN was evaluated previously using electrodes aimed ϳ0.8 mm dorsolateral to the MRN (Dudley et al, 1999). Stimulation from these electrodes did not affect SCN 5-HT release; therefore, it is unlikely that passive current flow from electrodes in the DRN would affect MRN neurons located farther away (ϳ2.0 mm ventral) from the stimulation site.…”

“…Diffusion of drugs between the DRN and MRN was evaluated by comparing responses of the different nuclei with the same doses of drugs. The differential effects obtained [i.e., threefold greater response to 8-OH-DPAT or WAY 100635 injections into the MRN versus the DRN (Dudley et al, 1999)] indicate that the effects of the drugs were registered primarily at the site of injection. Also, the lack of effect of DRN injections that were off target by ϳ1 mm supports this contention.…”

“…Mapping studies reveal that the MRN is the sole source of SCN serotonergic innervation (Vertes and Kocsis, 1994;Moga and Moore, 1997). Nevertheless, stimulation of the DRN produces 5-HT-related effects in the SCN, including inhibition of light-induced Fos expression (Meyer-Bernstein and and neuronal discharge (Yu et al, 1997), attenuation of light-induced phase shifts (Weber et al, 1998), and 5-HT release (Dudley et al, 1999). These findings, together with the raphe-SCN mapping results, suggest that the DRN communicates with the SCN via a multisynaptic interaction through the MRN.…”

Role for theClockGene in Bipolar Disorder

“…Other studies have shown that serotonin neurons from the midbrain raphe nuclei innervate the SCN, and local applications of 5-hydroxytryptamine (5-HT) or 5-HT1A and 5-HT7 receptor agonists to the SCN will also produce a phase-advance in circadian activity (Dudley et al 1999;Ehlen et al 2001). Thus, it is possible that antidepressants in the selective serotonin reuptake inhibitor (SSRI) class may also exert some of their effects on depression through modulation of the circadian clock.…”