In vivo resetting of the hamster circadian clock by 5-HT7 receptors in the suprachiasmatic nucleus.
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-HT(1A,7) receptor 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 inhibitor para-chlorophenylalanine. Phase advances induced by SCN 8-OH-DPAT perfusion were significantly inhibited by the 5-HT(2,7) receptor antagonist ritanserin and by the more selective 5-HT(7) receptor antagonist DR4004, implicating the 5-HT(7) 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-HT(7) 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.
Ehlen
J C
JC
Department of Biological Sciences, Kent State University, Kent, Ohio 44242, USA.
Grossman
G H
GH
Glass
J D
JD
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage; D000818:Animals; D001683:Biological Clocks / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D002851:Chromatography, High Pressure Liquid; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D006224:Cricetinae; D010134:Fenclonine / Q000008:administration & dosage; D007279:Injections, Subcutaneous; D008027:Light; D008297:Male; D008647:Mesocricetus; D017551:Microdialysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects / Q000528:radiation effects; D010477:Perfusion; D010775:Photic Stimulation; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000008:administration & dosage; D012702:Serotonin Antagonists / Q000008:administration & dosage; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage; D013493:Suprachiasmatic Nucleus / Q000187:drug effects / Q000378:metabolism*; D013779:Tetrodotoxin / Q000008:administration & dosage
D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C104425:serotonin 7 receptor; D012701:Serotonin; D013779:Tetrodotoxin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D010134:Fenclonine