title: Levetiracetam has no significant gamma-aminobutyric acid-related effect on paired-pulse interaction in the dentate gyrus of rats.
abstract: Gamma-aminobutyric acid (GABA)ergic mechanisms of the novel antiepileptic drug, levetiracetam (Keppra), have been both favored and rejected. Since paired-pulse interaction is accepted in functionally assessing GABAergic mechanisms, we investigated whether levetiracetam affects the paired-pulse inhibition/facilitation of the field potentials, evoked in the dentate gyrus of urethane-anesthesized rats. This model revealed a strong paired-pulse inhibition at 20-ms interstimulus interval, a noteworthy paired-pulse facilitation at 80-ms interstimulus interval, and a moderate paired-pulse inhibition at 500-ms interstimulus interval. Bicuculline (3 mg/kg/h, i.v.) and baclofen (10 mg/kg, i.v.) markedly depressed paired-pulse inhibition at 20-ms interstimulus interval, while clonazepam (1 mg/kg, i.p.), diazepam (10 mg/kg, i.v.), and phenobarbital (40 mg/kg, i.v.) enhanced it. Bicuculline also depressed paired-pulse inhibition at 500-ms interstimulus interval. Bicuculline, baclofen, and diazepam reduced paired-pulse facilitation at 80-ms interstimulus interval. Distinct from these GABA(A) receptor- and GABA(B) receptor-related drugs, levetiracetam (17 and 540 mg/kg, i.v.) had no significant effect on either paired-pulse interaction in this model, a result not favoring any major role of GABAergic mechanisms in its antiseizure action.
authors.affiliation: UCB S.A. Pharma Sector, Research and Development, Preclinical CNS Research, Chemin du Foriest, B-1420 Braine-l'Alleud, Belgium. Doru.Margineanu@ucb-group.com
authors.forename: Doru Georg
authors.initials: DG
authors.lastname: Margineanu
authors.forename: Henrik
authors.initials: H
authors.lastname: Klitgaard
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001418:Baclofen / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D002998:Clonazepam / Q000494:pharmacology; D003292:Convulsants / Q000494:pharmacology; D018891:Dentate Gyrus / Q000187:drug effects* / Q000502:physiology; D003975:Diazepam / Q000494:pharmacology; D004558:Electric Stimulation; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D000077287:Levetiracetam; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects*; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D003292:Convulsants; D018755:GABA Agonists; D018756:GABA Antagonists; D018079:Receptors, GABA; D000077287:Levetiracetam; D005680:gamma-Aminobutyric Acid; D002998:Clonazepam; D001418:Baclofen; D003975:Diazepam; D001640:Bicuculline; D010634:Phenobarbital; D010889:Piracetam