Glass J David, Grossman Gregory H, Farnbauch Laure, DiNardo Lisa
Department of Biological Sciences, Kent State University, Kent, Ohio 44242-0001, USA.
J Neurosci. 2003 Aug 20;23(20):7451-60. doi: 10.1523/JNEUROSCI.23-20-07451.2003.
Serotonin (5-HT) is an important regulator of the mammalian circadian clock of the suprachiasmatic nucleus (SCN); however, critical questions remain concerning the control of serotonergic activity in the SCN and how this relates to the putative clock-resetting actions of 5-HT. Previously, we reported that electrical stimulation of the dorsal raphe nucleus (DRN) or median raphe nucleus (MRN) in hamsters evoked 5-HT release in the SCN. This DRN-stimulated 5-HT release was blocked by systemic injection of 5-HT antagonists, indicating a 5-HT receptor-mediated pathway from the DRN to the SCN. In the present study, targeted injections of the 5-HT1,2,7 antagonist metergoline or the selective 5-HT7 antagonist DR4004 into the DRN or MRN attenuated DRN-electrically stimulated SCN 5-HT release, supporting a multisynaptic DRN-->MRN-->SCN route. Intra-DRN and intra-MRN injections of the GABA(A) antagonist bicuculline significantly stimulated SCN 5-HT release, whereas intra-DRN or intra-MRN injections of the GABAA agonist muscimol suppressed this release. The 5-HT release induced by intra-DRN bicuculline was also blocked by co-injection of DR4004. In complementary behavioral trials, SCN 5-HT release associated with a phase-advancing sleep deprivation stimulus at midday was prevented by intra-DRN injection of metergoline. Also, phase-advance shifts induced by novel wheel access at midday were suppressed, but not blocked, by intra-DRN injection of DR4004 or muscimol. These results indicate that 5-HT7 and GABAergic receptors of the DRN and MRN regulate behaviorally induced 5-HT release in the SCN, and that DRN output modulates nonphotic phase-resetting responses.
血清素（5-羟色胺，5-HT）是哺乳动物视交叉上核（SCN）生物钟的重要调节因子；然而，关于SCN中血清素能活性的控制以及这与5-HT假定的生物钟重置作用之间的关系，仍存在关键问题。此前，我们报道过，电刺激仓鼠的中缝背核（DRN）或中缝正中核（MRN）会诱发SCN中5-HT的释放。这种由DRN刺激引起的5-HT释放可被全身注射5-HT拮抗剂所阻断，这表明存在一条从DRN到SCN的由5-HT受体介导的途径。在本研究中，将5-HT1、2、7拮抗剂美替拉酮或选择性5-HT7拮抗剂DR4004靶向注射到DRN或MRN中，可减弱DRN电刺激引起的SCN中5-HT的释放，这支持了一条多突触的DRN→MRN→SCN途径。向DRN和MRN内注射GABA(A)拮抗剂荷包牡丹碱可显著刺激SCN中5-HT的释放，而向DRN或MRN内注射GABAA激动剂蝇蕈醇则会抑制这种释放。DRN内注射荷包牡丹碱诱导的5-HT释放也会被同时注射DR4004所阻断。在补充性的行为试验中，DRN内注射美替拉酮可阻止与中午相位提前的睡眠剥夺刺激相关的SCN中5-HT的释放。此外，中午新的转轮活动诱导的相位提前变化可被DRN内注射DR4004或蝇蕈醇所抑制，但未被阻断。这些结果表明，DRN和MRN的5-HT7和GABA能受体调节行为诱导的SCN中5-HT的释放，并且DRN的输出调节非光性相位重置反应。
