Comparison of the Effects of Convulsant and Depressant Barbiturate Stereoisomers on AMPA-type Glutamate Receptors

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[Greek small letter 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 suppress 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 [Greek small letter gamma]-aminobutyric acid type A (GABAA) receptor-mediated currents to determine if the inhibitory effects on AMPA receptors correlate to the in vivo effects of the isomers.


The authors measured whole-cell currents in the rat cultured cortical neuron at holding potential of -60 mV. Kainate 500 [micro sign]M was applied as the agonist for AMPA receptors. Thiopental (3-300 [micro sign]M), R(-)-MPPB or S(+)-MPPB (100-1,000 [micro sign]M) was coapplied with kainate under the condition in which the GABAA receptor-mediated current was blocked. Effects of MPPB isomers on the current elicited by GABA 1 [micro sign]M were studied in the separate experiments.


Thiopental inhibited the kainate-induced current reversibly and in a dose-dependent manner, with a concentration for 50% inhibition of 49.3 [micro sign]M. Both R(-)-MPPB and S(+)-MPPB inhibited the kainate-induced current with a little stereoselectivity. R(-)-MPPB was slightly but significantly more potent than S(+)-MPPB. In contrast, R(-)-MPPB enhanced but S(+)-MPPB reduced the GABA-induced current.


Both convulsant and depressant stereoisomers of the barbiturate inhibited the AMPA receptor-mediated current despite of their opposite effects on 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 the barbiturates.

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