Jc. Ehlen et al., In vivo resetting of the hamster circadian clock by 5-HT7 receptors in thesuprachiasmatic nucleus, J NEUROSC, 21(14), 2001, pp. 5351-5357
Serotonin (5-HT) has been strongly implicated in the regulation of the mamm
alian circadian clock located in the suprachiasmatic nuclei (SCN); however,
its role in behavioral (nonphotic) circadian phase resetting remains elusi
ve. 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 a
ddressed this question using a novel reverse-microdialysis approach for tim
ed perfusions of serotonergic and other agents to the Syrian hamster SCN wi
th durations equivalent to the increases in in vivo 5-HT release during pha
se-resetting behavioral manipulations. We found that 3 hr perfusions of the
SCN with either 5-HT or the 5-HT1A,7 receptor agonist 2-dipropylamino-8-hy
droxy-1,2,3,4-tetrahydro-naphthalene (8-OH-DPAT) at midday advanced the pha
se 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-HT2,7 receptor antagonist ritanserin and
by the more selective 5-HT7 receptor antagonist DR4004, implicating the 5-H
T7 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 no
t suppress intra-SCN 8-OH-DPAT-induced phase advances. These results indica
te that 5-HT7 receptor-mediated phase resetting in the SCN is markedly infl
uenced by the degree of postsynaptic responsiveness to 5-HT and by photic s
timulation. Finally, 5-HT may act directly on SCN clock cells to induce in
vivo nonphotic phase resetting.