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 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 gamma-aminobutyric acid type A (GABA(A)) receptor-mediated currents to determine if the inhibitory effects on AMPA receptors correlate to the in vivo effects of the isomers.


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


RESULTS
Thiopental inhibited the kainate-induced current reversibly and in a dose-dependent manner, with a concentration for 50% inhibition of 49.3 microM. 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.


CONCLUSIONS
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.
Kamiya
Y
Y
Department of Anesthesiology, Yokohama City University School of Medicine, Japan.
Andoh
T
T
Furuya
R
R
Hattori
S
S
Watanabe
I
I
Sasaki
T
T
Ito
H
H
Okumura
F
F
D000818:Animals; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003292:Convulsants / Q000494:pharmacology*; D007608:Kainic Acid / Q000494:pharmacology; D010634:Phenobarbital / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000187:drug effects*; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology; D013237:Stereoisomerism; D013696:Temperature; D013874:Thiopental / Q000494:pharmacology*
D002492:Central Nervous System Depressants; D003292:Convulsants; D018091:Receptors, AMPA; D011963:Receptors, GABA-A; C008555:1-methyl-5-phenyl-5-propylbarbituric acid; D013874:Thiopental; D007608:Kainic Acid; D010634:Phenobarbital