Serotonin (5-HT) has been strongly implicated in the regulation of the mammalian circadian clock located in the suprachiasmatic nuclei (SCN); however, its role in behavioral (nonphotic) circadian phase resetting remains elusive. Central to this issue are divergent lines of evidence that the SCN may, or may not, be a target for the phase-resetting effects of 5-HT. We have addressed this question using a novel reverse-microdialysis approach for timed perfusions of serotonergic and other agents to the Syrian hamster SCN with durations equivalent to the increases in in vivo 5-HT release during phase-resetting behavioral manipulations. We found that 3 hr perfusions of the SCN with either 5-HT or the 5-HT1A,7receptor agonist 2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydro-naphthalene (8-OH-DPAT) at midday advanced the phase of the free-running circadian rhythm of wheel-running assessed using an Aschoff type II procedure. Phase shifts induced by 8-OH-DPAT were enhanced more than threefold by pretreatment with the 5-HT synthesis inhibitorpara-chlorophenylalanine. Phase advances induced by SCN 8-OH-DPAT perfusion were significantly inhibited by the 5-HT2,7 receptor antagonist ritanserin and by the more selective 5-HT7 receptor antagonist DR4004, implicating the 5-HT7 receptor in mediating this phase resetting. Concurrent exposure to light during the 8-OH-DPAT perfusion abolished the phase advances. Furthermore, coperfusion of the SCN with TTX, which blocked in vivo 5-HT release, did not suppress intra-SCN 8-OH-DPAT-induced phase advances. These results indicate that 5-HT7 receptor-mediated phase resetting in the SCN is markedly influenced by the degree of postsynaptic responsiveness to 5-HT and by photic stimulation. Finally, 5-HT may act directly on SCN clock cells to induce in vivo nonphotic phase resetting.
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