Presynaptic actions of propofol enhance inhibitory synaptic transmission in isolated solitary tract nucleus neurons

Young Ho Jin, Zhenxiong Zhang, David Mendelowitz, Michael C. Andresen

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

General anesthetics variably enhance inhibitory synaptic transmission that relies on (-aminobutyric acid (GABA) and GABAA receptor function with distinct differences across brain regions. Activation of "extra-synaptic" GABAA receptors produces a tonic current considered the most sensitive target for general anesthetics, particularly in forebrain neurons. To evaluate the contribution of poor drug access to neurons in slices, we tested the intravenous anesthetic propofol in mechanically isolated neurons from the solitary tract nucleus (NTS). Setting chloride concentrations to ECl = - 29 mV made GABA currents inward at holding potentials of - 60 mV. Propofol triggered pronounced but slowly-developing tonic currents that reversed with 5 min washing. Effective concentrations in isolated cells were lower than in slices and propofol enhanced phasic IPSCs more potently than tonic currents (1 μM increased phasic decay-time constant vs. > 3 μM tonic currents). Propofol increased IPSC frequency (> 3 μM), a presynaptic action. Bicuculline blocked all propofol actions. Gabazine blocked only phasic IPSCs. IPSCs persisted in TTX and/or cadmium but these agents prevented propofol-induced increases in IPSC frequency. Furosemide (> 1 mM) reversibly blocked propofol-evoked IPSC frequency changes without altering waveforms. We conclude that presynaptic actions of propofol depend on a depolarizing chloride gradient across presynaptic inhibitory terminals. Our results in isolated neurons indicate that propofol pharmacokinetics intrinsically trigger the tonic currents slowly and the time course is not related to slow permeation or delivery. Unlike forebrain, phasic NTS GABAA receptors are more sensitive to propofol than tonic receptors but that presynaptic GABAA receptor mechanisms regulate GABA release.

Original languageEnglish (US)
Pages (from-to)75-83
Number of pages9
JournalBrain research
Volume1286
DOIs
StatePublished - Aug 25 2009

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Keywords

  • Anesthetic
  • Autonomic
  • Brainstem
  • GABA

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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