Serotonin (5-HT) and 5-HT receptor agonists can modify the response of the mammalian suprachiasmatic nucleus (SCN) to light. It remains uncertain which 5-HT receptor subtypes mediate these effects. The effects of 5-HT receptor activation on optic nerve–mediated input to SCN neurons were examined using whole-cell patch-clamp recordings in horizontal slices of ventral hypothalamus from the male mouse. The hypothesis that 5-HT reduces the effect of retinohypothalamic tract (RHT) input to the SCN by acting at 5-HT1B receptors was tested first. As previously described in the hamster, a mixed 5-HT1A/1B receptor agonist, 1-[3-(trifluoromethyl)phenyl]-piperazine hydrochloride (TFMPP), reduced the amplitude of glutamatergic excitatory postsynaptic currents (EPSCs) evoked by selectively stimulating the optic nerve of wild-type mice. The agonist was negligibly effective in a 5-HT1B receptor knockout mouse, suggesting minimal contribution of 5-HT1A receptors to the TFMPP-induced reduction in the amplitude of the optic nerve–evoked EPSC. We next tested the hypothesis that 5-HT also reduces RHT input to the SCN via activation of 5-HT7 receptors. The mixed 5-HT1A/7 receptor agonist, R(+)-8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT), reduced the evoked EPSC amplitude in both wild-type and 5-HT1B receptor knockout mice. This effect of 8-OH-DPAT was minimally attenuated by the selective 5-HT1A receptor antagonist WAY 100635 but was reversibly and significantly reduced in the presence of ritanserin, a mixed 5-HT2/7 receptor antagonist. Taken together with the authors' previous ultrastructural studies of 5-HT1B receptors in the mouse SCN, these results indicate that in the mouse, 5-HT reduces RHT input to the SCN by acting at 5-HT1Breceptors located on RHT terminals. Moreover, activation of 5-HT7 receptors in the mouse SCN, but not 5-HT1A receptors, also results in a reduction in the amplitude of the optic nerve–evoked EPSC. The findings indicate that 5-HT may modulate RHT glutamatergic input to the SCN through 2 or more 5-HT receptors. The likely mechanism of altered RHT glutamatergic input to SCN neurons is an alteration of photic effects on the SCN circadian oscillator.
Adham N, Zgombick JM, Bard J, and Branchek TA (1998) Functional characterization of the recombinant human 5-hydroxytryptamine7(A) receptor isoform coupled to adenylate cyclase stimulation. J Pharmacol Exp ther287:508-514.
2.
Azmitia EC and Segal M (1978) An autoradiographic analysis of differential ascending projections of the dorsal and median raphe nuclei of the rat. J Comp Neurol179: 641-668.
3.
Barnes NM and Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacol38:1083-1152.
4.
Belenky MA and Pickard GE (2001) Subcellular distribution of 5-HT1B and 5-HT7 receptors in the mouse suprachiasmatic nucleus. Forthcoming.
5.
Cahill GM and Menaker M (1989) Effects of excitatory amino acid receptor antagonists and agonists on suprachiasmatic nucleus responses to retinohypothalamic tract volleys. Brain Res479:76-82.
6.
Castel M, Belenky MA, Cohen S, Ottersen OP, and Storm-Mathisen J (1993) Glutamate-like immunoreactivity in retinal terminals of the mouse suprachiasmatic nucleus. Eur J Neurosci5:368-381.
7.
Charest A, Wainer BH, and Albert PR (1993) Cloning and differentiation-induced expression of a murine serotonin1A receptor in a septal cell line. J Neurosci13: 5164-5171.
8.
Colwell CS, Foster RG, and Menaker M (1991) NMDAreceptor antagonists block the effects of light on circadian behavior in the mouse. Brain Res554:105-110.
9.
Cushing DJ, Zgombick JM, Nelson DL, and Cohen ML (1996) LY215840, a high-affinity 5-HT7 receptor ligand, blocks serotonin-induced relaxation in canine coronary artery. J Pharmacol Exp ther277:1560-1566.
10.
Cutrera RA, Ouarour A, and Pevet P (1994) Effects of the 5HT1A receptor agonist 8-OH-DPAT and other non-photic stimuli on the circadian rhythm of wheel-running activity in hamsters under different constant conditions. Neurosci Lett172:27-30.
11.
Duncan MJ, Jennes L, Jefferson JB, and Brownfield MS (2000) Localization of serotonin5A receptors in discrete regions of the circadian timing system in the Syrian hamster. Brain Res869:178-185.
12.
Duncan MJ, Short J, and Wheeler DL (1999) Comparison of the effects of aging on 5-HT7 and 5-HT1A receptors in discrete regions of the circadian timing system in hamsters. Brain Res829:39-45.
13.
Ebling FJP (1996) The role of glutamate in the photic regulation of the suprachiasmatic nucleus. Prog Neurobiol50:109-132.
14.
Edgar DM, Miller JD, Prosser RA, Dean RR, and Dement WC (1993) Serotonin and the mammalian circadian system: II. Phase shifting rat behavioral rhythms with serotonergic agonists. J Biol Rhythms8:17-31.
15.
Erlander MG, Lovenberg TW, Baron BM, DeLuca L, Danielson PE, Racke M, Slone AL, Siegel BW, Foye PE, Cannon K, and others (1993) Two members of a distinct subfamily of 5-hydroxytryptamine receptors differentially expressed in rat brain. Proc Natl Acad Sci U S A90:3452-3456.
16.
Fletcher A, Forster EA, Bill DJ, Brown G, Cliffe IA, Hartley JE, Jones DE, Mc Lenachan A, Stanhope KJ, Critchley DJP, and others (1996) Electrophysiological, biochemical, neurohormonal, and behavioral studies with WAY-100635, a potent, selective, and silent 5-HT1A receptor antagonist. Behav Brain Res73:337-353.
17.
Forbes IT, Dabbs S, Duckworth DM, Jennings AJ, King FD, Lovell PJ, Brown AM, Collin L, Hagan JJ, Middlemiss DN, and others (1998) (R)-3, N-Dimethyl-N-[1-methyl-3-(4-methyl-piperidin-1-yl)propyl]benzenesulfonamide: The first selective 5-HT7 receptor antagonist. J Med Chem41:655-657.
18.
Fornal CA, Metzler CW, Gallegos RA, Veasey SC, McCreary AC, and Jacobs BL(1996) WAY-100635, a potent and selective 5-hydroxytryptamine1A antagonist, increases serotonergic neural activity in behaving cats: Comparison with (S)-WAY-100135. J Pharmacol Exp ther278:752-762.
19.
Forster EA, Cliffe IA, Bill DJ, Dover GM, Jones D, Reilly Y, and Fletcher A (1995) A pharmacological profile of the selective silent 5-HT1A receptor antagonist, WAY-100635. Eur J Pharmacol281:81-88.
20.
Glass JD, Selim M, and Rea MA (1994) Modulation of light-induced C-Fos expression in the suprachiasmatic nuclei by 5-HT1A receptor agonists. Brain Res638:235-242.
21.
Grailhe R, Waeber C, Dulawa SC, Hornung JP, Zhuang X, Brunner D, Geyer MA, and Hen R (1999) Increased exploratory activity and altered response to LSD in mice lacking the 5-HT(5A) receptor. Neuron22:581-591.
22.
Gustafson EL, Durkin MM, Bard JA, Zgombick J, and Branchek TA (1996) A receptor autoradiographic and in situ hybridization analysis of the distribution of the 5-ht7receptor in rat brain. Br J Pharmacol117:657-666.
23.
Heidmann DEA, Szot P, Kohen R, and Hamblin MW (1998) Function and distribution of three rat 5-hydroxy-tryptamine7 (5-HT7) receptor isoforms produced by alternate splicing. Neuropharmacol37:1621-1632.
24.
Hery M, Francois-Bellan AM, Hery F, Deprez P, and Becquet D (1997) Serotonin directly stimulates luteinizing hormone-releasing hormone from GT1 cells via 5-HT7 receptors. Endocrine7:261-265.
25.
Horikawa K, Yokota S, Fuji K, Akiyama M, Moriya T, Okamura H, and Shibata S (2000) Nonphotic entrainment by 5-HT1A/7 receptor agonists accompanied by reduced Per1 and Per2 mRNA levels in the suprachiasmatic nuclei. J Neurosci20:5867-5873.
26.
Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, and Humphrey PPA (1994) VII. International union of pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacol Rev46:157-203.
27.
Jiang ZG, Teshima K, Yang Y, Yoshioka T, and Allen CN (2000) Pre and postsynaptic actions of serotonin on rat suprachiasmatic nucleus neurons. Brain Res866:247-256.
28.
Jiang ZG, Yang Y, Liu ZP, and Allen CN (1997) Membrane properties and synaptic inputs of suprachiasmatic nucleus neurons in rat brain slices. J Physiol (London)499:141-159.
29.
Kawahara F, Saito H, and Katsuki H (1994) Inhibition by 5-HT7 receptor stimulation of GABAA receptor-activated current in cultured rat suprachiasmatic neurones. J Neurophysiol478:67-73.
30.
Kia HK, Miquel MC, Brisorgueil MJ, Daval G, Riad M, Mestikawy SE, Hamon M, and Verge D (1996) Immunocytochemical localization of serotonin1A receptors in the rat central nervous system. J Comp Neurol365:289-305.
31.
Kikuchi C, Nagaso H, Hiranuma T, and Koyama M (1999) Tetrahydrobenzindoles: Selective antagonists of the 5-HT7 receptor. J Med Chem42:533-535.
32.
Kim YI and Dudek FE (1991) Intracellular electrophysiological study of suprachiasmatic nucleus neurons in rodents: Excitatory synaptic mechanisms. J Physiol44:269-287.
33.
Knobelman DA, Kung HF, and Lucki I (2000) Regulation of extracellular concentrations of 5-hydroxytryptamine (5-HT) in mouse striatum by 5-HT(1A) and 5-HT(1B) receptors. J Pharmacol Exp ther292:1111-1117.
34.
Kohler M, Kalkowski A, and Wollnik F (1999) Serotonin agonist quipazine induces photic-like phase shifts of the circadian activity rhythm and c-fos expression in the rat suprachiasmatic nucleus. J Biol Rhythms14:131-140.
35.
Lovenberg TW, Baron BM, deLecea L, Miller JD, Prosser RA, Rea MA, Foye PE, Racke M, Slone AL, Siegel BW, and others (1993) A novel adenylyl cyclase-activating serotonin receptor (5-HT7) implicated in the regulation of mammalian circadian rhythms. Neuron11:449-458.
36.
Lucas JJ and Hen R (1995) New players in the 5-HT receptor field: Genes and knockouts. Trends Pharmacol Sci16: 248-252.
37.
Manrique C, Hery F, Faudon M, and Francois-Bellan AM (1999) Indirect evidence for an association of 5-HT1Bbinding sites with retinal and geniculate axon terminals in the rat suprachiasmatic nucleus. Synapse33:314-323.
38.
Manrique C, Segu L, Hery F, Hery M, Faudon M, and Francois-Bellan AM (1993) Increase of central 5HT1Bbinding sites following 5,7-dihydroxytryptamine axotomy in the adult rat. Brain Res623:345-348.
39.
Matthes H, Boschert U, Amlaiky N, Grailhe R, Plassat J, Muscatelli F, Mattei M, and Hen R (1993) Mouse 5-hydroxytryptamine5A and 5-hydroxytryptamine5Breceptors define a new family of serotonin receptors: Cloning, functional expression, and chromosomal localization. Mol Pharmacol43:313-319.
40.
Medanic M and Gillette MU (1992) Serotonin regulates the phase of the rat suprachiasmatic circadian pacemaker in vitro only during the subjective day. J Physiol450:629-642.
41.
Meyer-Bernstein EL and Morin LP (1996) Differential serotonergic innervation of the suprachiasmatic nucleus and the intergeniculate leaflet and its role in circadian rhythm modulation. J Neurosci16:2097-2111.
42.
Middlemiss DN and Fozard JR (1983) 8-hydroxy-2-(di-n-propylamino) tetralin discriminates between subtypes of the 5HT1 recognition site. Eur J Pharmacol90: 151-153.
43.
Middlemiss DN and Hutson PH (1990) The 5-HT1B receptors. Ann N Y Acad Sci600:132-148.
44.
Miller JD and Fuller CA (1990) The response of supra-chiasmatic neurons of the rat hypothalamus to photic and serotonergic stimulation. Brain Res515:155-162.
45.
Mooney RD, Shi MY, and Rhoades RW (1994) Modulation of retinotectal transmission by presynaptic 5-HT1B receptors in the superior colliculus of the adult hamster. J Neurophysiol72:3-13.
46.
Moore RY, Halaris AE, and Jones BA (1978) Serotonin neurons of the midbrain raphe: Ascending projections. J Comp Neurol180:417-438.
47.
Morin LP (1994) The circadian visual system. Brain Res Rev67:102-127.
48.
Morin LP(1999) Serotonin and the regulation of mammalian circadian rhythmicity. Ann Med31:12-33.
49.
Morin LP and Blanchard J (1991) Depletion of brain serotonin by 5,7-DHT modifies hamster circadian rhythm response to light. Brain Res566:1173-1185.
50.
Moyer RW and Kennaway DJ (1999) Immunohistochemical localization of serotonin receptors in the rat suprachiasmatic nucleus. Neurosci Lett271:147-150.
51.
Moyer RW, Kennaway DJ, Ferguson SA, and Dijstelbloem YP (1997) Quipazine and light have similar effects on c-fos induction in the rat suprachiasmatic nucleus. Brain Res765:337-342.
52.
Mundey MK, Fletcher A, and Marsden CA (1996) Effects of 8-OHDPAT and 5-HT1A antagonists WAY100135 and WAY100635, on guinea-pig behaviour and dorsal raphe 5-HT neurone firing. Br J Pharmacol117:750-756.
53.
Oliver KR, Kinsey AM, Wainwright A, and Sirinathsinghji DJS (2000) Localization of 5-ht5A receptor-like immunoreactivity in the rat brain. Brain Res867:131-142.
54.
Parks CL, Robinson PS, Sibille E, Shenk T, and Toth M (1998) Increased anxiety of mice lacking the serotonin1A receptor. Proc Natl Acad Sci U S A95:10734-10739.
55.
Peroutka SJ and Howell TA (1994) The molecular evolution of G protein-coupled receptors: Focus on 5-hydroxy-tryptamine receptors. Neuropharmacology33:319-332.
56.
Pickard GE and Rea MA(1997a) Serotonergic innervation of the hypothalamic suprachiasmatic nucleus and photic regulation of circadian rhythms. Biol Cell89:513-523.
57.
Pickard GE and Rea MA (1997b) TFMPP, a 5HT1B receptor agonist, inhibits light-induced phase shifts of the circadian activity rhythm and c-fos expression in the mouse suprachiasmatic nucleus. Neurosci Lett231:95-98.
58.
Pickard GE, Smith BN, Belenky M, Rea MA, Dudek FE, and Sollars PJ (1999) 5-HT1B receptor-mediated presynaptic inhibition of retinal input to the suprachiasmatic nucleus. J Neurosci19:4034-4045.
59.
Pickard, GE, Weber ET, Scott PA, Riberdy AF, and Rea MA (1996) 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. J Neurosci16:8208-8220.
60.
Plassat J-L, Amlaiky N, and Hen R (1993) Molecular cloning of a mammalian serotonin receptor that activates adenylate cyclase. Mol Pharmacol44:229-236.
61.
Prosser RA, Dean RR, Edgar DM, Heller HC, and Miller JD (1993) Serotonin and the mammalian circadian system: I. In vitro phase shifts by serotonergic agonists and antagonists. J Biol Rhythms8:1-16.
62.
Quintero JE and McMahon DG (1999) Serotonin modulates glutamate responses in isolated suprachiasmatic nucleus neurons. J Neurophysiol82:533-539.
63.
Ramboz S, Oosting R, Amara DA, Kung HF, Blier P, Mendelsohn M, Mann JJ, Brunner D, and Hen R (1998) Serotonin receptor 1A knockout: An animal model of anxiety-related disorder. Proc Natl Acad SciUSA95: 14476-14481.
64.
Rea MA, Barrera J, Glass JD, and Gannon RL (1995) Serotonergic potentiation of photic phase shifts of circadian activity rhythm. Neuroreport6:1417-1420.
65.
Rea MA, Glass JD, and Colwell CS (1994) Serotonin modulates photic responses in the hamster suprachiasmatic nuclei. J Neurosci14:3635-3642.
66.
Rea MA and Pickard GE (2000) A 5-HT1B receptor agonist inhibits light-induced suppression of pineal melatonin production. Brain Res858:424-428.
67.
Roca AL, Weaver DR, and Reppert SM (1993) Serotonin receptor gene expression in the rat suprachiasmatic nuclei. Brain Res608:159-165.
68.
Saudou F, Amara DA, Dierich A, LeMeur M, Ramboz S, Segu L, Buhot MC, and Hen R (1994) Enhanced aggressive behavior in mice lacking 5-HT1B receptor. Science265:1875-1878.
69.
Saudou F and Hen R (1994) 5-Hydroxytryptamine receptor subtypes in vertebrates and invertebrates. Neurochem Int25:503-532.
70.
Scott PA, Cagle M, and Rea MA (1996) Serotonin (5-HT) receptor binding and mRNA expression in the rat suprachiasmatic nucleus (SCN). Soc Neurosci22:1141-1141.
71.
Selim M, Glass JD, Hauser UE, and Rea MA (1993) Serotonergic inhibition of light-induced Fos protein expression and extracellular glutamate in the suprachiasmatic nuclei. Brain Res621:181-188.
72.
Shen Y, Monsma FJ, Metcalf MA, Jose PA, Hamblin MW, and Sibley DR (1993) Molecular cloning and expression of a 5-hyroxytryptamine7 serotonin receptor subtype. J Biol Chem268:18200-18204.
73.
Shibata S, Tsuneyoshi A, Hamada T, Tominaga K, and Watanabe S (1992) Phase resetting effect of 8-OH-DPAT, a serotonin 1Areceptor agonist, on the circadian rhythm of firing rate in the rat suprachiasmatic nuclei in vitro. Brain Res582:353-356.
74.
Smale L, Michels KM, Moore RY, and Morin LP (1990) Destruction of the hamster serotonergic system by 5,7-DHT: Effects on circadian rhythm phase, entrainment, and response to triazolam. Brain Res515:9-19.
75.
Smith BN, Banfield BW, Smeraski CA, Wilcox CL, Dudek FE, Enquist LW, and Pickard GE (2000) Pseudorabies virus expressing enhanced green fluorescent protein: Atool for in vitroelectrophysiological analysis of transsynaptically labeled neurons in identified central nervous system circuits. Proc Natl Acad Sci U S A97:9264-9269.
76.
Steinbusch HWM (1981) Distribution of serotoninimmunoreactivity in the central nervous system of the rat-cell bodies and terminals. Neuroscience6:557-618.
77.
Stowe RL and Barnes NM (1998) Selective labeling of 5-HT7receptor recognition sites in rat brain using [3H]5-carboxamidotryptamine. Neuropharmacology37:1611-1619.
78.
Sumner BEH, Rosie R, and Fink G (1992) Relative density of 5-hydroxytryptamine receptor subtype mRNAs in female rat neuroendocrine brain determined by in situ hybridization histochemistry. Mol Cell Neurosci3:215-223.
79.
Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, and Julius D (1995) Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors. Nature374:542-546.
80.
Tominaga K, Shibata S, Ueki S, and Watanabe S (1992) Effects of 5HT1A receptor agonists on the circadian rhythm of wheel-running activity in hamsters. Eur J Pharmacol214:79-84.
81.
Vanhoenacker P, Haegeman G, and Leysen J (2000) 5-HT7 receptors: Current knowledge and future prospects. Trends Pharmacol Sci21:70-77.
82.
Weber ET, Gannon RL, and Rea MA(1998) Local administration of serotonin agonists blocks light-induced phase advances of the circadian activity rhythm in the hamster. J Biol Rhythms13:209-218.
83.
Wood M, Chaubey M, Atkinson P, and Thomas DR (2000) Antagonist activity of meta-chlorophenylpiperazine and partial agonist activity of 8-OH-DPAT at the 5-HT7 receptor. Eur J Pharmacol396:1-8.
84.
Ying S-W and Rusak B (1994) Effects of serotonergic agonists on firing rates of photically responsive cells in the hamster suprachiasmatic nucleus. Brain Res651:37-46.
85.
Ying S-W and Rusak B (1997) 5-HT7 receptors mediate serotonergic effects of light-sensitive suprachiasmatic nucleus neurons. Brain Res755:246-254.
