title: Orexin neurons are directly and indirectly regulated by catecholamines in a complex manner.
abstract: We reported elsewhere that orexin neurons are directly hyperpolarized by noradrenaline (NA) and dopamine. In the present study, we show that NA, dopamine, and adrenaline all directly hyperpolarized orexin neurons. This response was inhibited by the alpha2 adrenergic receptor (alpha2-AR) antagonist, idazoxan or BRL44408, and was mimicked by the alpha2-AR-selective agonist, UK14304. A low concentration of Ba2+ inhibited NA-induced hyperpolarization, which suggests that activation of G protein coupled inward rectifier potassium channels is involved in the response. In the presence of a high concentration of idazoxan, NA induced depolarization or inward current. This response was inhibited by alpha1-AR antagonist, prazosin, which suggests the existence of alpha1-ARs on the orexin neurons along with alpha2-AR. We also examined the effects of NA on glutamatergic and GABAergic synaptic transmission. NA application dramatically increased the frequency and amplitude of spontaneous inhibitory synaptic currents (sIPSCs) and inhibited excitatory synaptic currents (sEPSCs) in orexin neurons; however, NA decreased the frequency of miniature EPSCs (mEPSCs) and IPSCs and the amplitude of evoked EPSCs and IPSCs through the alpha2-AR, because the NA response on mPSCs was inhibited by idazoxan. These results suggest that the NA-induced increase in sIPSC frequency and amplitude is mediated via alpha1-ARs on the somata of GABAergic neurons that innervate the orexin neurons. Calcium imaging using orexin/YC2.1 transgenic mouse brain revealed that NA-induced inhibition of orexin neurons is not altered by sleep deprivation or circadian time in mice. The evidence presented here revealed that orexin neurons are regulated by catecholamines in a complex manner.
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan. yamank@md.tsukuba.ac.jp
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yamanaka
authors.forename: Yo
authors.initials: Y
authors.lastname: Muraki
authors.forename: Kanako
authors.initials: K
authors.lastname: Ichiki
authors.forename: Natsuko
authors.initials: N
authors.lastname: Tsujino
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Kilduff
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Goto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakurai
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000502:physiology; D002395:Catecholamines / Q000502:physiology*; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000502:physiology; D019329:Idazoxan / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis* / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009474:Neurons / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology*; D009479:Neuropeptides / Q000032:analysis* / Q000502:physiology*; D009638:Norepinephrine / Q000502:physiology; D064446:Orexin Receptors; D000068797:Orexins; D018340:Receptors, Adrenergic, alpha-1 / Q000032:analysis / Q000502:physiology; D018341:Receptors, Adrenergic, alpha-2 / Q000032:analysis / Q000502:physiology; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D012892:Sleep Deprivation / Q000503:physiopathology; D009435:Synaptic Transmission / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis / Q000502:physiology
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D002395:Catecholamines; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D013779:Tetrodotoxin; D014446:Tyrosine 3-Monooxygenase; D002118:Calcium; D009638:Norepinephrine; D019329:Idazoxan