Orexins (hypocretins) directly excite tuberomammillary neurons

Eur J Neurosci. 2001 Nov;14(9):1571-5. doi: 10.1046/j.0953-816x.2001.01777.x.


Wakefulness has recently been shown to depend upon the newly identified orexin (or hypocretin) neuropeptides by the findings that alteration in their precursor protein, their receptors or the neurons that produce them leads to the sleep disorder narcolepsy in both animals and humans. The questions of how and where these brain peptides act to maintain wakefulness remain unresolved. The purpose of the present study was to determine whether the orexins could directly affect hypothalamic histaminergic neurons, which are known to contribute to the state of wakefulness by their diffuse projections through the brain. Using brain slices, we recorded in the ventral tuberomammillary nuclei from neurons identified as histaminergic on the basis of their previously described morphological and electrophysiological characteristics and found that they were depolarized and excited by the orexins through a direct postsynaptic action. We then compared the depolarizing effect of orexin A and B and found that they were equally effective upon these cells. This latter finding suggests that the effect of orexins is mediated by orexin type 2 receptors, which are those lacking in narcoleptic dogs. Our results therefore show that the histaminergic neurons of the tuberomammillary nuclei represent an important target for the orexin system in the maintenance of wakefulness.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects*
  • Action Potentials / physiology
  • Animals
  • Biotin / analogs & derivatives*
  • Carrier Proteins / metabolism
  • Carrier Proteins / pharmacology*
  • Efferent Pathways / cytology
  • Efferent Pathways / drug effects
  • Efferent Pathways / metabolism
  • Histamine / metabolism*
  • Hypothalamic Area, Lateral / cytology
  • Hypothalamic Area, Lateral / drug effects*
  • Hypothalamic Area, Lateral / metabolism
  • Intracellular Signaling Peptides and Proteins*
  • Molecular Probes
  • Narcolepsy / metabolism
  • Narcolepsy / pathology
  • Narcolepsy / physiopathology
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neuropeptides / metabolism
  • Neuropeptides / pharmacology*
  • Orexins
  • Organ Culture Techniques
  • Rats
  • Synapses / drug effects
  • Synapses / metabolism
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology
  • Wakefulness / drug effects*
  • Wakefulness / physiology


  • Carrier Proteins
  • HCRT protein, human
  • Intracellular Signaling Peptides and Proteins
  • Molecular Probes
  • Neuropeptides
  • Orexins
  • neurobiotin
  • Biotin
  • Histamine