Selective Enhancement of Synaptic Inhibition by Hypocretin (Orexin) in Rat Vagal Motor Neurons: Implications for Autonomic Regulation

J Neurosci. 2003 May 1;23(9):3844-54. doi: 10.1523/JNEUROSCI.23-09-03844.2003.

Abstract

The hypocretins (orexins) are hypothalamic neuropeptides implicated in feeding, arousal, and autonomic regulation. These studies were designed to determine the actions of hypocretin peptides on synaptic transmission in the dorsal motor nucleus of the vagus nerve (DMV). Whole-cell patch-clamp recordings were made from DMV neurons in transverse slices of rat brainstem. Some of the neurons were identified as gastric-related by retrograde labeling after inoculation of the stomach wall with pseudorabies virus 152, a viral label that reports enhanced green fluorescent protein. Consistent with previous findings, hypocretins caused an inward current (6-68 pA) in most neurons at holding potentials near rest. In addition, the frequency of spontaneous IPSCs was increased in a concentration-related manner (up to 477%), with little change in EPSCs. This effect was preserved in the presence of tetrodotoxin, suggesting a presynaptic site of action. Hypocretins increased the amplitude of IPSCs evoked by electrical stimulation of the nucleus tractus solitarius (NTS) but not evoked EPSCs. Hypocretin-induced increases in the frequency of IPSCs evoked by photoactivation of caged glutamate within the NTS were also observed. Identical effects of the peptides were observed in identified gastric-related and unlabeled DMV neurons. In contrast to some previous studies, which have reported primarily excitatory actions of the hypocretins in many regions of the CNS, these data support a role for hypocretin in preferentially enhancing synaptic inhibition, including inhibitory inputs arising from neurons in the NTS. These findings indicate that the hypocretins can modulate and coordinate visceral autonomic output by acting directly on central vagal circuits.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Brain Stem / cytology
  • Brain Stem / drug effects
  • Brain Stem / physiology
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / pharmacology*
  • Electric Stimulation
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Glutamates / pharmacology
  • Herpesvirus 1, Suid / physiology
  • In Vitro Techniques
  • Intracellular Signaling Peptides and Proteins*
  • Luminescent Proteins / biosynthesis
  • Luminescent Proteins / genetics
  • Male
  • Motor Neurons / drug effects
  • Motor Neurons / physiology*
  • Neural Inhibition / drug effects
  • Neural Inhibition / physiology*
  • Neuropeptides / biosynthesis
  • Neuropeptides / pharmacology*
  • Orexins
  • Patch-Clamp Techniques
  • Photochemistry
  • Rats
  • Rats, Sprague-Dawley
  • Solitary Nucleus / drug effects
  • Solitary Nucleus / physiology
  • Stimulation, Chemical
  • Stomach / innervation
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*
  • Vagus Nerve / cytology
  • Vagus Nerve / physiology*

Substances

  • (carboxy-2-nitrobenzyl)glutamic acid
  • Carrier Proteins
  • Glutamates
  • Intracellular Signaling Peptides and Proteins
  • Luminescent Proteins
  • Neuropeptides
  • Orexins