Midbrain raphe modulation of nonphotic circadian clock resetting and 5-HT release in the mammalian suprachiasmatic nucleus.
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.
Glass
J David
JD
Department of Biological Sciences, Kent State University, Kent, Ohio 44242-0001, USA. Jglass@kent.edu
Grossman
Gregory H
GH
Farnbauch
Laure
L
DiNardo
Lisa
L
D000818:Animals; D001522:Behavior, Animal; D001640:Bicuculline / Q000494:pharmacology; D002940:Circadian Rhythm; D006224:Cricetinae; D004558:Electric Stimulation; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008647:Mesocricetus; D008711:Metergoline / Q000494:pharmacology; D008959:Models, Neurological; D009118:Muscimol / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology*; D018079:Receptors, GABA / Q000502:physiology; D011985:Receptors, Serotonin / Q000502:physiology; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013493:Suprachiasmatic Nucleus / Q000378:metabolism*
C472242:DR-4004; D018755:GABA Agonists; D018756:GABA Antagonists; D007211:Indoles; D011725:Pyridines; D018079:Receptors, GABA; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor; D008711:Metergoline; D009118:Muscimol; D012701:Serotonin; D001640:Bicuculline