Inhibition by levetiracetam of a non-GABAA receptor-associated epileptiform effect of bicuculline in rat hippocampus.
1. Extracellular recording of field potentials, evoked by commissural stimulation in hippocampal area CA3 of anaesthetized rats, was performed in order to study the mode of action of the novel antiepileptic drug levetiracetam (ucb LO59). 2. The amplitude of orthodromic field population spike (PS2) markedly increased and repetitive population spikes appeared when the recording micropipette contained either bicuculline methiodide (BMI), or the specific GABAA antagonist gabazine (SR-95531). 3. BMI-induced increases in PS2 were reduced in a dose-dependent manner by 1 to 320 mumol kg-1 levetiracetam i.v., with a U-shape dose-response relationship. However, levetiracetam did not reduce the increases in PS2 produced by gabazine. 4. Clonazepam (1 mg kg-1, i.p.), carbamazepine (20 mg kg-1, i.p.) and valproate (200 mg kg-1, i.v.) were ineffective in preventing BMI-induced increases in PS2, while the calcium channel antagonist flunarizine, 50 mumol kg-1, i.p., reduced PS2 increments caused by BMI. The L-type calcium channel blocker nifedipine, 100 mumol kg-1, i.p., was without effect. Similar to levetiracetam, flunarizine did not reduce the increases in PS2 induced by gabazine. 5. These data suggest that the increased excitability of CA3 neurones, caused by BMI administered in situ, involves calcium-dependent processes not associated with blockade of GABAA receptors. The inhibition by levetiracetam of this calcium-dependent effect of BMI might contribute to the antiepileptic effects of the drug.
Margineanu
D G
DG
UCB s.a. Pharma Sector, Research & Development, Chemin du Foriest, Braine-l'Alleud, Belgium.
Wülfert
E
E
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001640:Bicuculline / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003292:Convulsants / Q000494:pharmacology; D005444:Flunarizine / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D000077287:Levetiracetam; D008297:Male; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*
D000927:Anticonvulsants; D003292:Convulsants; D018756:GABA Antagonists; D011724:Pyridazines; D011963:Receptors, GABA-A; D000077287:Levetiracetam; C049853:gabazine; D005444:Flunarizine; D001640:Bicuculline; D010889:Piracetam