Ž . Brain Research 755 1997 246–254 Research report 5-HT receptors mediate serotonergic effects on light-sensitive 7 suprachiasmatic nucleus neurons Shui-Wang Ying a , Benjamin Rusak a,b,c, ) a Department of Psychology, Life Sciences Centre, Dalhousie UniÕersity, Halifax, NoÕa Scotia B3H 4J1, Canada b Department of Psychiatry, Dalhousie UniÕersity, Halifax, NoÕa Scotia, Canada c Department of Pharmacology, Dalhousie UniÕersity, Halifax, NoÕa Scotia, Canada Accepted 30 December 1996 Abstract Ž . Serotonin 5-HT has been shown to phase shift circadian rhythms in mammals and to affect responses of the circadian system to light, but it is not clear which receptors are involved in these actions. We found that drugs which act as 5-HT receptor agonists suppressed 1A photic responses of hamster SCN cells, but these drugs also exhibit high affinity for the recently cloned 5-HT receptor. We therefore 7 studied the effects of 5-HT agonists and antagonists with differential affinities for 5-HT and 5-HT receptors on responses of hamster 7 1A SCN cells to retinal illumination. We confirmed that the 5-HT receptor agonists 5-HT, 8-OH-DPAT and 5-CT, dose-dependently reduced photic activation of SCN cells. These effects could be blocked by co-application of antagonists with high affinities for 5-HT receptors: 7 ritanserin or clozapine. The 5-HT antagonist, cyanopindolol, which is inactive at 5-HT receptors, did not antagonize the actions 1ArBrD 7 of 8-OH-DPAT. Selective 5-HT antagonists, WAY100635 and p-MPPI, had weak or no antagonist effects on the responses to 1A 8-OH-DPAT in the SCN, but they effectively antagonized the actions of 8-OH-DPAT in the hippocampus. In the cerebellar cortex where few 5-HT receptors are present, ritanserin failed to antagonize the effects of 8-OH-DPAT. Our results indicate that the 5-HT receptor 7 7 subtype plays a major role in mediating the effects of 5-HT on photic responses of SCN cells in the hamster. Keywords: 5-HT ; 5-HT ; Agonist; Antagonist; Serotonin; Suprachiasmatic nucleus; Hippocampus; Cerebellum; Light; Entrainment; Photic response 7 1A 1. Introduction Ž . The suprachiasmatic nucleus SCN of the hypothala- mus functions as the dominant pacemaker for behavioral and physiological circadian rhythms in mammals. Photic information required for entrainment to lighting cycles reaches the SCN through the direct retinohypothalamic tract and the geniculohypothalamic tract, originating in the w x retinorecipient intergeniculate leaflet 1–5,51 . The SCN also receives dense serotonergic projections from the raphe w x nuclei 6–10 . Serotonergic neurons in the dorsal raphe project to the intergeniculate leaflet, while those in the median raphe project to the SCN and are involved in w x regulating circadian rhythms in hamsters 11 . Drugs active Ž . at serotonin 5-HT receptors have been shown to phase- w x shift circadian rhythms of wheel-running activity 12–15 w x and of neuronal activity in SCN slice preparations 16–19 , w x to modulate spontaneous 20 and light-evoked activity of ) Ž . Corresponding author. Fax: q1 902 494-2159r6585; E-mail: rusak@is.dal.ca w x SCN cells 8,21,22 , and to inhibit light-induced Fos pro- w x tein expression in the SCN 23 . In addition, damage to the 5-HT projection to the SCN can alter photic entrainment of w x circadian rhythms in rodents 24,25 . At least 14 subtypes of 5-HT receptor have been identi- fied and classified into seven families, based on their gene structure, the degree of homology of amino acid se- quences, signal transduction mechanisms, and functional w x characteristics 26–28 . It remains uncertain, however, Ž. which 5-HT receptor subtype s is involved in regulating photic responses of SCN cells. In a previous study, we found that iontophoretic appli- cation of the 5-HT receptor agonists 5-HT, 8-hydroxy-di- Ž . propylaminotetralin 8-OH-DPAT and 5-carboxa- Ž . midotryptamine 5-CT to photically responsive SCN cells w x suppressed firing rates 22 . These effects were attenuated by a nonselective 5-HT antagonist, metergoline, in most cells tested, and the effects of 8-OH-DPAT were also attenuated by a putative 5-HT antagonist, SDZ 216-525 1A w x 29 . We, therefore, concluded that 5-HT agonists affected SCN cell firing rates by acting on a 5-HT -like receptor. 1A 0006-8993r97r$17.00 Copyright q 1997 Elsevier Science B.V. All rights reserved. Ž . PII S0006-8993 97 00102-9