5-HT7 receptors mediate serotonergic effects on light-sensitive suprachiasmatic nucleus neurons

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-HT1A receptor agonists suppressed photic responses of hamster SCN cells, but these drugs also exhibit high affinity for the recently cloned 5-HT7 receptor. We therefore studied the effects of 5-HT agonists and antagonists with differential affinities for 5-HT7 and 5-HT1A receptors on responses of hamster 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-HT7 receptors: ritanserin or clozapine. The 5-HT1A/B/D antagonist, cyanopindolol, which is inactive at 5-HT7 receptors, did not antagonize the actions of 8-OH-DPAT. Selective 5-HT1A antagonists, WAY100635 and p-MPPI, had weak or no antagonist effects on the responses to 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-HT7 receptors are present, ritanserin failed to antagonize the effects of 8-OH-DPAT. Our results indicate that the 5-HT7 receptor subtype plays a major role in mediating the effects of 5-HT on photic responses of SCN cells in the hamster.