title: Presynaptic actions of general anesthetics are responsible for frequency-dependent modification of synaptic transmission in the rat hippocampal CA1.
abstract: BACKGROUND
  In clinical anesthesia, robust surgical stress occasionally causes unintended light anesthesia during operation. To test the hypothesis that neural input condition could modify actions of general anesthetics as a result of presynaptic alteration in the central nervous system, we investigated the mechanisms by which the stimulus frequency modifies synaptic transmission of the rat hippocampus in the presence of general anesthetics.
  
  
  METHODS
  Field population spikes (PSs) of CA1 pyramidal neurons were elicited using orthodromic stimulation of Schaffer collateral-commissural fibers (test-pulse). A second stimulating electrode was placed in the region of the alveus hippocampi to activate recurrent inhibition of area CA1 (pre-pulse). The pre-pulses were applied as train stimuli (100-200 Hz) to activate release and then deplete the neurotransmitter (gamma-aminobutyric acid [GABA]) at presynaptic terminals of inhibitory interneurons.
  
  
  RESULTS
  After the activation of inhibitory interneurons with pre-pulses, both IV (thiopental and pentobarbital) and volatile (sevoflurane and isoflurane) anesthetics attenuated the PS amplitudes elicited with test-pulses (test-PS). The IV anesthetics, but not the volatile drugs, produced stimulus frequency- and use-dependent recurrent inhibition of test-PSs. Neither a GABA type A agonist nor a GABA uptake inhibitor produced frequency-dependent modification. The pre-pulse train protocol revealed that IV anesthetics, but not volatile drugs, can enhance GABA release from presynaptic terminals.
  
  
  CONCLUSIONS
  IV anesthetics, but not volatile drugs, enhance the discharge of a readily releasable pool of GABA vesicles from presynaptic terminals. Depletion of an active pool of GABA after high-frequency stimuli would produce frequency- and use-dependent recurrent inhibition in the presence of IV anesthetics. The stimulus frequency-dependent modification of synaptic transmission might be responsible for the unsuccessful immobilization or hypnosis during general anesthesia after IV anesthetic administration.
authors.affiliation: Department of Anesthesiology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, 2633 Sugitani, Toyama 930-0194, Japan. koki@med.u-toyama.ac.j
authors.forename: Koki
authors.initials: K
authors.lastname: Hirota
authors.forename: Rika
authors.initials: R
authors.lastname: Sasaki
authors.forename: Sheldon H
authors.initials: SH
authors.lastname: Roth
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Yamazaki
mesh_terms: D018681:Anesthetics, General / Q000494:pharmacology*; D000818:Animals; D001369:Axons / Q000502:physiology; D056547:CA1 Region, Hippocampal / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D002490:Central Nervous System / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004594:Electrophysiology; D058785:GABA-A Receptor Agonists; D007530:Isoflurane / Q000494:pharmacology; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D017966:Pyramidal Cells / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017661:Receptors, Presynaptic / Q000187:drug effects* / Q000378:metabolism; D000077149:Sevoflurane; D009435:Synaptic Transmission / Q000187:drug effects*; D013874:Thiopental / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018681:Anesthetics, General; D058785:GABA-A Receptor Agonists; D008738:Methyl Ethers; D018377:Neurotransmitter Agents; D014179:Neurotransmitter Uptake Inhibitors; D017661:Receptors, Presynaptic; D000077149:Sevoflurane; D005680:gamma-Aminobutyric Acid; D007530:Isoflurane; D013874:Thiopental