THE EFFECT OF PROPOFOL ON CA1 PYRAMIDAL CELL EXCITABILITY AND GABA(A)-MEDIATED INHIBITION IN THE RAT HIPPOCAMPAL SLICE

An in vitro paired-pulse orthodromic stimulation technique was used to examine the effects of propofol on excitatory afferent terminals, CA1 pyramidal cells and recurrent collateral evoked inhibition in the rat hippocampal slice. Hippocampal slices 400 mu m thick were perfused wi th oxygenated artificial cerebrospinal fluid, and electrodes were plac ed in the CAI region to record extracellular field population spike (P S) or excitatory postsynaptic potential (EPSP) responses to stimulatio n of Schaffer collateral/commissural fibers. Gamma-aminobutyric acid ( GABA)-mediated recurrent inhibition was measured using a paired-pulse technique. The major effect of propofol (7-28 mu M) was a dose and tim e dependent increase in the intensity and duration of GABA-mediated in hibition. This propofol effect could be rapidly and completely reverse d by exposure to known GABA(A) antagonists, including picrotoxin, bicu culline and pentylenetetrazol. It was also reversed by the chloride ch annel antagonist, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DI DS). It was not antagonized by central (flumazenil) or peripheral (PK1 1195) benzodiazepine antagonists. Reversal of endogenous inhibition wa s also noted with the antagonists picrotoxin and pentylenetetrazol. In put/output curves constructed using stimulus propofol caused only a sm all enhancement of EPSPs at higher stimulus intensities but had no eff ect on PS amplitudes. These studies are consistent with propofol havin g a GABA(A)-chloride channel mechanism causing its effect on recurrent collateral evoked inhibition in the rat hippocampal slice.