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 Previous Article
Volume 16, Number 24,
Issue of December 15, 1996
pp. 8208-8220
Copyright ©1996 Society for Neuroscience
5HT1B Receptor Agonists Inhibit Light-Induced Phase
Shifts of Behavioral Circadian Rhythms and Expression of the
Immediate-Early Gene c-fos in the Suprachiasmatic
Nucleus
Received June 17, 1996; revised Sept. 24, 1996; accepted Oct. 3, 1996.
Gary E. Pickard1, 2,
E.
Todd Weber1,
Paul A. Scott1,
Anne F. Riberdy1, and
Michael A. Rea1, 3
1 Biological Rhythms and Integrative Neuroscience
Institute, Armstrong Laboratory (CFTO), Brooks Air Force Base, Texas
78235-5104, 2 Department of Psychiatry, University of
Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6141, and 3 Department of Pharmacology, University of Texas
Health Science Center at San Antonio, San Antonio, Texas 78229-7764
The suprachiasmatic nucleus (SCN) is a circadian oscillator and a
critical component of the mammalian circadian system. It receives
afferents from the retina and the mesencephalic raphe. Retinal
afferents mediate photic entrainment of the SCN, whereas the
serotonergic afferents originating from the midbrain modulate photic
responses in the SCN; however, the serotonin (5HT) receptor subtypes in
the SCN responsible for these modulatory effects are not well
characterized. In this study, we tested the hypothesis that
5HT1B receptors are located presynaptically on retinal axon terminals in the SCN and that activation of these receptors inhibits retinal input.
The 5HT1B receptor agonists TFMPP and CGS 12066A,
administered systemically, inhibited light-induced phase shifts of the
circadian activity rhythm in a dose-dependent manner at phase delay and phase advance time points. This inhibition was not affected by previous
systemic application of either the selective 5HT1A receptor antagonist (+)WAY 100135 or by the 5HT2 receptor antagonist
mesulergine, whereas pretreatment with the nonselective
5HT1 antagonist methiothepin significantly attenuated the
effect of TFMPP. TFMPP also produced a dose-dependent reduction in
light-stimulated Fos expression in the SCN, although a small subset of
cells in the dorsolateral aspect of the caudal SCN were
TFMPP-insensitive. TFMPP (1 mM) infused into the SCN
produced complete inhibition of light-induced phase advances. Finally,
bilateral orbital enucleation reduced the density of SCN
5HT1B receptors as determined using
[125I]-iodocyanopindolol to define 5HT1B
binding sites. These results are consistent with the interpretation
that 5HT1B receptors are localized presynaptically on
retinal terminals in the SCN and that activation of these receptors by
5HT1B agonists inhibits retinohypothalamic input.
Key words:
suprachiasmatic nucleus;
circadian rhythm;
presynaptic;
5HT1B;
TFMPP;
CGS 12066A;
c-fos;
photic
entrainment;
retinal afferents;
[125I]-iodocyanopindolol
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