Effects on synaptic inhibition in the hippocampus do not underlie the amnestic and convulsive properties of the nonimmobilizer 1,2-dichlorohexafluorocyclobutane.
BACKGROUND
Although it does not suppress movement in response to noxious stimuli, the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (F6, also known as 2N) does cause amnesia and seizures. These occur at 0.48 and 1.3 times, respectively, the concentrations that are predicted from its lipid solubility to cause immobility. The molecular and cellular basis of these effects is not known. The ionotropic gamma-aminobutyric acid type A (GABAA) receptor is modulated strongly by anesthetics, and it plays an important role in many seizure models. Also, the hippocampus is a structure central to the formation of memory and is susceptible to seizure generation. The authors therefore investigated the effect of F6 on GABAA receptor- mediated inhibition in hippocampal neurons.


METHODS
Transverse hippocampal slices were prepared from young (12- to 21-day-old) Sprague-Dawley rats. Inhibitory postsynaptic currents were recorded from hippocampal CA1 pyramidal cells in the presence of ionotropic glutamate receptor antagonists. F6 was applied with the bath solution. The concentration of F6 achieved during the experiment at the location of synaptic inhibition was derived using a diffusion model.


RESULTS
At tissue concentrations of up to 75 microm (approximately 5 x predicted minimal alveolar concentration), F6 had no discernible effect on either the amplitude or the kinetics of GABA-mediated synaptic currents. Isoflurane, by contrast, prolonged the decay time constant of these currents at 100 microm (approximately 0.3 x minimal alveolar concentration).


CONCLUSIONS
At concentrations that bracket the in vivo amnestic and seizure-inducing range, F6 has no discernible effect on fast synaptic GABAA receptors in hippocampal CA1 pyramidal neurons. Synaptic GABAA receptors sharply discriminate between volatile anesthetics and a prototype nonimmobilizer. Similar in vivo effects of anesthetics and nonimmobilizers may be mediated by different cellular mechanisms.
Perouansky
Misha
M
Department of Anesthesiology, University of Wisconsin, Madison, Wisconsin 53792-3272, USA. mperouansky@wiscmail.wisc.edu
Pearce
Robert A
RA
D000647:Amnesia / Q000139:chemically induced*; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D002849:Chromatography, Gas; D003503:Cyclobutanes / Q000494:pharmacology*; D004594:Electrophysiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects*; D007530:Isoflurane / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D018408:Patch-Clamp Techniques; D011712:Pyramidal Tracts / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced*; D013569:Synapses / Q000187:drug effects*
C488074:1,2-dichlorohexaflurocyclobutane; D018685:Anesthetics, Inhalation; D003503:Cyclobutanes; D011963:Receptors, GABA-A; D007530:Isoflurane