Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline).
Dorsal raphe serotonin neurons fire tonically at a low rate during waking. In vitro, however, they are not spontaneously active, indicating that afferent inputs are necessary for tonic firing. Agonists of three arousal-related systems impinging on the dorsal raphe (orexin/hypocretin, histamine and the noradrenaline systems) caused an inward current and increase in current noise in whole-cell patch-clamp recordings from these neurons in brain slices. The inward current induced by all three agonists was significantly reduced in extracellular solution containing reduced sodium (25.6 mm). In extracellular recordings, all three agonists increased the firing rate of serotonin neurons; the excitatory effects of histamine and orexin A were occluded by previous application of phenylephrine, suggesting that all three systems act via common effector mechanisms. The dose-response curve for orexin B suggested an effect mediated by type II (OX2) receptors. Single-cell PCR demonstrated the presence of both OX1 and OX2 receptors in tryptophan hydroxylase-positive neurons. The effects of histamine and the adrenoceptor agonist, phenylephrine, were blocked by antagonists of histamine H1 and alpha1 receptors, respectively. The inward current induced by orexin A and phenylephrine was not blocked by protein kinase inhibitors or by thapsigargin. Three types of current-voltage responses were induced by all three agonists but in no case did the current reverse at the potassium equilibrium potential. Instead, in many cases the orexin A-induced current reversed in calcium-free medium at a value (-23 mV) consistent with the activation of a mixed cation channel (with relative permeabilities for sodium and potassium of 0.43 and 1, respectively).
Brown
Ritchie E
RE
Institut für Neurophysiologie, Heinrich-Heine-Universität, D-40001 Düsseldorf, Germany. Ritchie_Brown@hms.harvard.edu
Sergeeva
Olga A
OA
Eriksson
Krister S
KS
Haas
Helmut L
HL
D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001143:Arousal / Q000187:drug effects / Q000502:physiology*; D002352:Carrier Proteins / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009479:Neuropeptides / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D064446:Orexin Receptors; D000068797:Orexins; D018408:Patch-Clamp Techniques; D016133:Polymerase Chain Reaction / Q000379:methods; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D012701:Serotonin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012964:Sodium / Q000378:metabolism; D014851:Wakefulness / Q000502:physiology
D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D064446:Orexin Receptors; D000068797:Orexins; D018340:Receptors, Adrenergic, alpha-1; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D012701:Serotonin; D006632:Histamine; D012964:Sodium; D009638:Norepinephrine