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

Aug 22, 2003The Journal of neuroscience : the official journal of the Society for Neuroscience

Midbrain serotonin system influences non-light resetting of the body’s daily clock and serotonin release in the brain’s timekeeping center

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Abstract

Targeted injections of the 5-HT1,2,7 antagonist metergoline significantly reduced serotonin release in the suprachiasmatic nucleus (SCN) in response to electrical stimulation of the dorsal raphe nucleus (DRN).

Serotonin is a key regulator of the mammalian circadian clock located in the SCN.
Electrical stimulation of the DRN or median raphe nucleus (MRN) induces serotonin release in the SCN.
This serotonin release pathway from the DRN to the SCN appears to involve multiple synapses.
Blocking GABA(A) receptors in the DRN or MRN increases serotonin release in the SCN.
Behavioral studies show that serotonin release in the SCN during sleep deprivation is inhibited by metergoline injections into the DRN.
Phase-advance shifts caused by novel wheel access are partially suppressed by injections of the 5-HT7 antagonist DR4004 or the GABA(A) agonist muscimol into the DRN.

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Serotonin (5-HT) is an important regulator of the mammalian circadian clock of the suprachiasmatic nucleus (SCN); however, critical questions remain concerning the control of serotonergic activity in the SCN and how this relates to the putative clock-resetting actions of 5-HT. Previously, we reported that electrical stimulation of the dorsal raphe nucleus (DRN) or median raphe nucleus (MRN) in hamsters evoked 5-HT release in the SCN. This DRN-stimulated 5-HT release was blocked by systemic injection of 5-HT antagonists, indicating a 5-HT receptor-mediated pathway from the DRN to the SCN. In the present study, targeted injections of the 5-HT1,2,7 antagonist metergoline or the selective 5-HT7 antagonist DR4004 into the DRN or MRN attenuated DRN-electrically stimulated SCN 5-HT release, supporting a multisynaptic DRN-->MRN-->SCN route. Intra-DRN and intra-MRN injections of the GABA(A) antagonist bicuculline significantly stimulated SCN 5-HT release, whereas intra-DRN or intra-MRN injections of the GABAA agonist muscimol suppressed this release. The 5-HT release induced by intra-DRN bicuculline was also blocked by co-injection of DR4004. In complementary behavioral trials, SCN 5-HT release associated with a phase-advancing sleep deprivation stimulus at midday was prevented by intra-DRN injection of metergoline. Also, phase-advance shifts induced by novel wheel access at midday were suppressed, but not blocked, by intra-DRN injection of DR4004 or muscimol. These results indicate that 5-HT7 and GABAergic receptors of the DRN and MRN regulate behaviorally induced 5-HT release in the SCN, and that DRN output modulates nonphotic phase-resetting responses.

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

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