The mechanisms of action of
antiepileptic drugs effective against
generalized absence seizures (antiabsence AEDs) remain uncertain. Antiabsence AEDs are generally effective against
seizures induced in experimental animals by
pentylenetetrazol (PTZ) and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (
DMCM), drugs which reduce GABAergic inhibition. Thus, antiabsence AEDs have been suggested to enhance GABAergic inhibition. We studied the effects of several AEDs on
GABA responses recorded from mouse spinal cord neurons grown in primary dissociated cell culture. Four antiabsence AEDs were included:
ethosuximide (ESM),
dimethadione (DMO),
sodium valproate (VPA), and
diazepam (DZP). Two experimental AEDs,
CGS 9896 and
ZK 91296, with
anticonvulsant action against PTZ- or
DMCM-induced
seizures were also included. Possible effects of the antiabsence and experimental AEDS on PTZ- and
DMCM-induced inhibition of
GABA responses were also evaluated. PTZ and
DMCM reversibly reduced
GABA responses in a concentration-dependent manner. PTZ completely inhibited
GABA responses
at 10 mM (IC50 of 1.1 mM), whereas
DMCM-induced inhibition of
GABA responses reached a plateau level of 39% of control values at 1 microM (IC50 of 33 nM). ESM (1,200 microM), DMO (6 mM), VPA (200 microM),
CGS 9896 (2 microM), and ZK 9896 (2 microM) did not alter
GABA responses. DZP enhanced
GABA responses in a concentration-dependent manner. The inhibition of
GABA responses produced by PTZ 1 mM was unaltered by ESM (600 microM), DMO (6 mM),
CGS 9896 (1 microM), or ZK 9896 (1 microM). Coapplication of VPA (200 microM) and PTZ (1 mM) slightly enhanced the PTZ effect. DZP (greater than 10 nM), however, reversed the PTZ-induced reduction of
GABA responses.(ABSTRACT TRUNCATED AT 250 WORDS)