A comparison of the anticonvulsant effects of 1,4- and 1,5-benzodiazepines in the amygdala-kindled rat and their effects on motor function.
Studies suggest that the 1,5-benzodiazepine clobazam possesses a favorable anticonvulsant profile due to its minimal neurotoxicity. The anticonvulsant and motor impairment effects of clobazam and 2 1,4-benzodiazepine, diazepam and clonazepam, were compared by dose-response analysis in amygdala-kindled rats and on 3 tests of motor function: gross motor impairment, a vertical screen test, and muscle tone. All drugs produced a significant, dose-dependent decrease in the duration of both behavioral and electrographic kindled seizure measures. Forelimb clonus suppression was the most sensitive measure of anticonvulsant drug effect. The order of potency for all effects was clonazepam greater than diazepam greater than clobazam. ED50s for the benzodiazepines' effects on motor impairment were compared to their ability to protect rats from forelimb clonus. Different spectrums of action for the various benzodiazepines were found depending on the comparison measure. Clonazepam had the most favorable ratio of potency for anticonvulsant vs. motor impairment activity when ataxia rating was the comparison measure. Diazepam had the most advantageous profile when the more sensitive screen test was used for comparison. Clobazam was not found to have a superior spectrum of action when compared across these measures. The results emphasize the importance of dose-response analyses and the consideration of behavioral measures used to assess beneficial and adverse effects of anticonvulsants.
Tietz
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EI
Department of Pharmacology, Medical College of Ohio, Toledo 43699.
Rosenberg
H C
HC
Chiu
T H
TH
D000679:Amygdala / Q000503:physiopathology*; D000818:Animals; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines; D001570:Benzodiazepinones / Q000009:adverse effects / Q000627:therapeutic use*; D000078306:Clobazam; D002998:Clonazepam / Q000009:adverse effects / Q000627:therapeutic use*; D003975:Diazepam / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D007696:Kindling, Neurologic; D008297:Male; D009069:Movement Disorders / Q000139:chemically induced*; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000188:drug therapy* / Q000503:physiopathology
D014151:Anti-Anxiety Agents; D001570:Benzodiazepinones; D001569:Benzodiazepines; D000078306:Clobazam; D002998:Clonazepam; D003975:Diazepam