Comparison of the effects of convulsant and depressant barbiturate stereoisomers on AMPA-type glutamate receptors

Background: alpha-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA )-type glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system. Although barbiturates have been shown to suppr ess the AMPA receptor-mediated responses, it is unclear whether this effect contributes to the anesthetic action of barbiturates. The authors compared the effects of depressant [R(-)] and convulsant [S(+)] stereoisomers of 1- methyl-5-phenyl-5-propyl barbituric acid (MPPB) on the AMPA and gamma-amino butyric acid type A (GABA(A)) receptor-mediated currents to determine if th e inhibitory effects on AMPA receptors correlate to the in vivo effects of the isomers. Method: The authors measured whole-cell currents in the rat cultured cortic al neuron at holding potential of -60 mV. Kainate 500 mu M mas applied as t he agonist for AMPA receptors. Thiopental (3-300 mu M), R(-)-MPPB or S(+)-M PPB (100-1,000 mu M) was coapplied with kainate under the condition in whic h the GABA, receptor-mediated current was blocked. Effects of MPPB isomers on the current elicited by GABA 1 mu M were studied in the separate experim ents. Results: Thiopental inhibited the kainate-induced current reversibly and in a dose-dependent manner, with a concentration for 50% inhibition of 49.3 m u M. Both R(-)-MPPB and S(S)-MPPB inhibited the kainate-induced current wit h a little stereoselectivity. R(-)-MPPB was slightly but significantly more potent than S(+)-MPPB. In contrast, R(-)-,MPPB enhanced but S(+)-MPPB redu ced the GABA-induced current. Conclusions: Both convulsant and depressant stereoisomers of the barbiturat e inhibited the AMPA receptor-mediated current despite of their opposite ef fects oil the central nervous system in vivo. Although thiopental exhibited a considerable inhibition of AMPA receptors, the results suggest that the inhibition of AMPA receptors contributes little to the hypnotic action of t he barbiturates.