Cholinergic modulation of narcoleptic attacks in double orexin receptor knockout mice

Mike Kalogiannis, Emily Hsu, Jon T. Willie, Richard M. Chemelli, Yaz Y. Kisanuki, Masashi Yanagisawa, Christopher S. Leonard

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

To investigate how cholinergic systems regulate aspects of the sleep disorder narcolepsy, we video-monitored mice lacking both orexin (hypocretin) receptors (double knockout; DKO mice) while pharmacologically altering cholinergic transmission. Spontaneous behavioral arrests in DKO mice were highly similar to those reported in orexin-deficient mice and were never observed in wild-type (WT) mice. A survival analysis revealed that arrest lifetimes were exponentially distributed indicating that random, Markovian processes determine arrest lifetime. Low doses (0.01, 0.03 mg/kg, IP), but not a high dose (0.08 mg/kg, IP) of the cholinesterase inhibitor physostigmine increased the number of arrests but did not alter arrest lifetimes. The muscarinic antagonist atropine (0.5 mg/kg, IP) decreased the number of arrests, also without altering arrest lifetimes. To determine if muscarinic transmission in pontine areas linked to REM sleep control also influences behavioral arrests, we microinjected neostigmine (50 nl, 62.5 μM) or neostigmine + atropine (62.5 μM and 111 μM respectively) into the nucleus pontis oralis and caudalis. Neostigmine increased the number of arrests in DKO mice without altering arrest lifetimes but did not provoke arrests in WT mice. Co-injection of atropine abolished this effect. Collectively, our findings establish that behavioral arrests in DKO mice are similar to those in orexin deficient mice and that arrests have exponentially distributed lifetimes. We also show, for the first time in a rodent narcolepsy model, that cholinergic systems can regulate arrest dynamics. Since perturbations of muscarinic transmission altered arrest frequency but not lifetime, our findings suggest cholinergic systems influence arrest initiation without influencing circuits that determine arrest duration.

Original languageEnglish (US)
Article numbere18697
JournalPLoS One
Volume6
Issue number4
DOIs
StatePublished - 2011

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Orexin Receptors
cholinergic agents
Knockout Mice
Cholinergic Agents
Modulation
Neostigmine
receptors
mice
Atropine
neostigmine
atropine
Narcolepsy
Physostigmine
Muscarinic Antagonists
Cholinesterase Inhibitors
Random processes
physostigmine
cholinesterase inhibitors
REM Sleep
Survival Analysis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Kalogiannis, M., Hsu, E., Willie, J. T., Chemelli, R. M., Kisanuki, Y. Y., Yanagisawa, M., & Leonard, C. S. (2011). Cholinergic modulation of narcoleptic attacks in double orexin receptor knockout mice. PLoS One, 6(4), [e18697]. https://doi.org/10.1371/journal.pone.0018697

Cholinergic modulation of narcoleptic attacks in double orexin receptor knockout mice. / Kalogiannis, Mike; Hsu, Emily; Willie, Jon T.; Chemelli, Richard M.; Kisanuki, Yaz Y.; Yanagisawa, Masashi; Leonard, Christopher S.

In: PLoS One, Vol. 6, No. 4, e18697, 2011.

Research output: Contribution to journalArticle

Kalogiannis, M, Hsu, E, Willie, JT, Chemelli, RM, Kisanuki, YY, Yanagisawa, M & Leonard, CS 2011, 'Cholinergic modulation of narcoleptic attacks in double orexin receptor knockout mice', PLoS One, vol. 6, no. 4, e18697. https://doi.org/10.1371/journal.pone.0018697
Kalogiannis, Mike ; Hsu, Emily ; Willie, Jon T. ; Chemelli, Richard M. ; Kisanuki, Yaz Y. ; Yanagisawa, Masashi ; Leonard, Christopher S. / Cholinergic modulation of narcoleptic attacks in double orexin receptor knockout mice. In: PLoS One. 2011 ; Vol. 6, No. 4.
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