Cholinergic regulation of orexin/hypocretin neurons through M(3) muscarinic receptor in mice.
The cholinergic system plays an important role in regulation of arousal and REM sleep. In the present study, we showed that a muscarinic receptor agonist, carbachol (CCh), activates almost 20% of orexin-producing neurons (orexin neurons), which play a critical role in maintenance of arousal. We also found that a very small population of orexin neurons (1%) was inhibited by CCh. Muscarinic receptor antagonists inhibited the CCh-induced activation of orexin neurons in a dose-dependent manner. The M(3)-selective muscarinic receptor antagonist 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP) affected the response at a significantly lower concentration compared with the M(1)-selective muscarinic antagonist pirenzepine. IC(50) of 4-DAMP and pirenzepine was 0.30 +/- 0.15 and 59.9 +/- 18.6 nM, respectively. The CCh-induced inward current was attenuated by the nonselective cation channel blocker SKF96365. These results indicate that CCh activates 20% of orexin neurons through the M(3) muscarinic receptor and subsequent activation of nonselective cation channels.
Ohno
Kousaku
K
Department of Pharmacology, Institute of Basic Medical Sciences, University of Tsukuba, Japan.
Hondo
Mari
M
Sakurai
Takeshi
T
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D027682:Cation Transport Proteins / Q000502:physiology; D002795:Choline O-Acetyltransferase / Q000032:analysis; D007026:Hypothalamic Area, Lateral / Q000201:enzymology / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009479:Neuropeptides / Q000502:physiology*; D000068797:Orexins; D043587:Receptor, Muscarinic M3 / Q000502:physiology*; D012895:Sleep, REM / Q000502:physiology
D027682:Cation Transport Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D043587:Receptor, Muscarinic M3; D002217:Carbachol; D002795:Choline O-Acetyltransferase