Presynaptic actions of propofol enhance inhibitory synaptic transmission in isolated solitary tract nucleus neurons.
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 microM increased phasic decay-time constant vs. >3 microM tonic currents). Propofol increased IPSC frequency (>3 microM), 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.
Jin
Young-Ho
YH
Department of Physiology, Kyung Hee University, Seoul 130-701, Republic of Korea.
Zhang
Zhenxiong
Z
Mendelowitz
David
D
Andresen
Michael C
MC
D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002478:Cells, Cultured; D005665:Furosemide / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000187:drug effects*; D015742:Propofol / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D017552:Solitary Nucleus / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects*
D018686:Anesthetics, Intravenous; D018756:GABA Antagonists; D011724:Pyridazines; D011963:Receptors, GABA-A; D049994:Sodium Potassium Chloride Symporter Inhibitors; D005665:Furosemide; C049853:gabazine; D001640:Bicuculline; D015742:Propofol