Effects of gamma-aminobutyric acid (GABA) receptor agonists on the neurotoxicity and anticonvulsant activity of barbiturates in mice

RA Ulloque, AY Chweh and EA Swinyard

The effects of gamma-aminobutyric acid (GABA) receptor agonists [4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol THIP]; [progabide and baclofen] on the minimal neurotoxicity and anticonvulsant activity of pentobarbital and phenobarbital in mice were investigated. When either progabide, THIP or baclofen were administered with pentobarbital, the components of this combination interacted additively by the rotorod test. Combinations of pentobarbital and progabide or phenobarbital and progabide interacted additively when subjected to the pentylenetetrazol (PTZ) minimal threshold seizure (clonic) test. THIP, even at toxic doses, did not alter the anti-PTZ activity of either pentobarbital or phenobarbital. In contrast, baclofen at toxic doses potentiated the anti-PTZ activity of pentobarbital and phenobarbital. Combinations of progabide and pentobarbital or progabide and phenobarbital interacted additively by the maximal electroshock seizure (MES) test. THIP, even when given in toxic doses, had no effect on the anti-MES activity of pentobarbital and phenobarbital. However, baclofen at nontoxic doses potentiated the anti-MES activity of phenobarbital but not that of pentobarbital. These results suggest that 1) in vitro interactions between barbiturates and GABAa receptor agonists may not be the same in vivo, 2) GABAa receptors may play a minor role in the minimal neurotoxicity and anticonvulsant activity of barbiturates and 3) inhibition of glutamate-induced excitation by baclofen may be an important action in potentiating the anti-MES activity of phenobarbital.

Volume 237, Issue 2, pp. 468-472, 05/01/1986
Copyright © 1986 by American Society for Pharmacology and Experimental Therapeutics