5HT(1B) RECEPTOR AGONISTS INHIBIT LIGHT-INDUCED PHASE-SHIFTS OF BEHAVIORAL CIRCADIAN-RHYTHMS AND EXPRESSION OF THE IMMEDIATE-EARLY GENE C-FOS IN THE SUPRACHIASMATIC NUCLEUS

The suprachiasmatic nucleus (SCN) is a circadian oscillator and a crit ical component of the mammalian circadian system. It receives afferent s from the retina and the mesencephalic raphe. Retinal afferents media te photic entrainment of the SCN, whereas the serotonergic afferents o riginating from the midbrain modulate photic responses in the SCN; how ever, the serotonin (5HT) receptor subtypes in the SCN responsible for these modulatory effects are not well characterized. In this study, w e tested the hypothesis that 5HT(1B) receptors are located presynaptic ally on retinal axon terminals in the SCN and that activation of these receptors inhibits retinal input. The 5HT(1B) receptor agonists TFMPP and CGS 12066A, administered systemically, inhibited light-induced ph ase 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 5HT (1A) receptor antagonist (+)WAY 100135 or by the 5HT(2) receptor antag onist mesulergine, whereas pretreatment with the nonselective 5HT(1) a ntagonist methiothepin significantly attenuated the effect of TFMPP. T FMPP also produced a dose-dependent reduction in light-stimulated Fos expression in the SCN, although a small subset of cells in the dorsola teral aspect of the caudal SCN were TFMPP-insensitive. TFMPP (1 mM) in fused into the SCN produced complete inhibition of light-induced phase advances. Finally, bilateral orbital enucleation reduced the density of SCN 5HT(1B) receptors as determined using [I-125]-iodocyanopindolol to define 5HT(1B) binding sites. These results are consistent with th e interpretation that 5HT(1B) receptors are localized presynaptically on retinal terminals in the SCN and that activation of these receptors by 5HT(1B) agonists inhibits retinohypothalamic input.