Effect of GABA agonists on the neurotoxicity and anticonvulsant activity of benzodiazepines.
Progabide (50 mg/kg, i.p.), a GABA receptor agonist, significantly decreases the median minimal neurotoxic dose (TD50) of clobazam, chlordiazepoxide, and diazepam; the receptor binding of these substances is highly enhanced by muscimol. Progabide has no significant effect on the TD50 of clonazepam and triazolam; the receptor bindings of these substances is either only slightly enhanced or not altered by muscimol. Progabide also significantly decreases the median antimaximal electroshock dose (MES ED50) of all the benzodiazepines tested. However, progabide has no effect on the median antipentylenetetrazol dose (PTZ ED50) of the benzodiazepines. Likewise, THIP (2.5 mg/kg, i.p.) significantly decreases the TD50 of chlordiazepoxide but not that of triazolam. THIP significantly decreases the MES ED50 of chlordiazepoxide and triazolam but has no effect on the PTZ ED50 of these two substances. The above data suggest that benzodiazepine receptors linked to GABA receptors contribute to the minimal neurotoxicity and anti-MES activity but not to the anti-PTZ activity of benzodiazepines.
Chweh
A Y
AY
Swinyard
E A
EA
Wolf
H H
HH
Kupferberg
H J
HJ
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D004357:Drug Synergism; D004597:Electroshock; D005445:Flunitrazepam / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D009118:Muscimol / Q000494:pharmacology; D009420:Nervous System / Q000187:drug effects*; D011963:Receptors, GABA-A / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*
D000927:Anticonvulsants; D007555:Isoxazoles; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D009118:Muscimol; C017985:progabide; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam; C015542:gaboxadol