Effects of antiepileptic drugs on GABA responses and on reduction of GABA responses by PTZ and DMCM on mouse neurons in cell culture.
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)
De Deyn
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PP
Department of Neurology, University of Michigan Medical Center, Ann Arbor.
Macdonald
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RL
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002243:Carbolines / Q000494:pharmacology*; D002478:Cells, Cultured; D018756:GABA Antagonists; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010433:Pentylenetetrazole / Q000494:pharmacology*; D013116:Spinal Cord / Q000166:cytology; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D000927:Anticonvulsants; D002243:Carbolines; D018756:GABA Antagonists; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D005680:gamma-Aminobutyric Acid; D010433:Pentylenetetrazole