title: Propofol facilitates glutamatergic transmission to neurons of the ventrolateral preoptic nucleus.
abstract: BACKGROUND
  There is much evidence that the sedative component of anesthesia is mediated by gamma-aminobutyric acid type A (GABA(A)) receptors on hypothalamic neurons responsible for arousal, notably in the tuberomammillary nucleus. These GABA(A) receptors are targeted by gamma-aminobutyric acid-mediated (GABAergic) neurons in the ventrolateral preoptic area (VLPO): When these neurons become active, they inhibit the arousal-producing nuclei and induce sleep. According to recent studies, propofol induces sedation by enhancing VLPO-induced synaptic inhibition, making the target cells more responsive to GABA(A). The authors explored the possibility that propofol also promotes sedation less directly by facilitating excitatory inputs to the VLPO GABAergic neurons.
  
  
  METHODS
  Spontaneous excitatory postsynaptic currents were recorded from VLPO cells-principally mechanically isolated, but also in slices from rats.
  
  
  RESULTS
  In isolated VLPO GABAergic neurons, propofol increased the frequency of glutamatergic spontaneous excitatory postsynaptic currents without affecting their mean amplitude. The action of propofol was mimicked by muscimol and prevented by gabazine, respectively a specific agonist and antagonist at GABA(A) receptors. It was also suppressed by bumetanide, a blocker of Na-K-Cl cotransporter-mediated inward Cl transport. In slices, propofol also increased the frequency of spontaneous excitatory postsynaptic currents and, at low doses, accelerated firing of VLPO cells.
  
  
  CONCLUSIONS
  Propofol induces sedation, at least in part, by increasing firing of GABAergic neurons in the VLPO, indirectly by activation of GABA(A) receptors on glutamatergic afferents: Because these axons/terminals have a relatively high internal Cl concentration, they are depolarized by GABAergic agents such as propofol, which thus enhance glutamate release.
authors.affiliation: Department of Anesthesiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Ke Y
authors.initials: KY
authors.lastname: Li
authors.forename: Yan-zhong
authors.initials: YZ
authors.lastname: Guan
authors.forename: Kresimir
authors.initials: K
authors.lastname: Krnjević
authors.forename: Jiang H
authors.initials: JH
authors.lastname: Ye
mesh_terms: D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D004594:Electrophysiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D005971:Glutamates / Q000502:physiology*; D066298:In Vitro Techniques; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D011301:Preoptic Area / Q000166:cytology* / Q000187:drug effects; D015742:Propofol / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D018686:Anesthetics, Intravenous; D000779:Anesthetics, Local; D018755:GABA Agonists; D018756:GABA Antagonists; D005971:Glutamates; D028021:Sodium-Potassium-Chloride Symporters; D002104:Cadmium; D013779:Tetrodotoxin; D015742:Propofol