Effects of compounds acting on GABA(B) receptors in the pentylenetetrazolekindling model of epilepsy in mice

The involvement of GABA(B) receptors in the behavioural and epileptic elect rocortical discharges occurring in chemical kindling induced by repeated tr eatments with a subconvulsant dose of pentylenetetrazole (25 mg/kg i.p.) ha s been investigated in CD1 mice. Behavioural and electrocorticographic epil eptic seizures following kindling induced by pentylenetetrazole (25 mg/kg i .p.) were attenuated or completely antagonized in a dose-dependent manner b y the GABA(B) receptor agonist R-baclofen (2 and 6 mg/kg) whilst the GABA(B ) receptor antagonist 3-amino-propyl-diethoxy-methyl-phosphinic acid (CGP 3 5348, 25, 50 or 100 mg/kg) and 3-[1-(S)-(3,4-dichloro-phenyl-ethyl]amino-2- hydroxy-propyl-benzyl-phosininic acid (CGP 55845A, 10 or 20 mg/kg) produced a more rapid development of kindling and an increase in behavioural and el ectrocorticographic epileptic changes. In addition, all GABA(B) receptor an tagonists were able to induce an increase in Fos and Jun protein expression in pentylenetetrazole (25 mg/kg i.p.) treated mice whilst the GABA(B) rece ptor agonist R-baclofen (2 or 6 mg/kg) attenuated the expression of Fos and Jun protein, at cortical and limbic structures. In order to study the pers istence of changes induced by pentylenetetrazole kindling, different groups of mice were rechallenged with a kindling stimulus 15 or 30 days after wit hdrawal from the last injection of vehicle+pentylenetetrazole, R-baclofen+p entylenetetrazole or GABA(B) receptor antagonists+pentylenetetrazole. The g roups receiving GABA(B) receptor antagonists+pentylenetetrazole showed a hi gher incidence of seizures following the kindling stimulus than mice receiv ing vehicle+pentylenetetrazole whilst animals treated with R-baclofen were protected from the kindling stimulus. The different effects observed follow ing repeated treatment with the GABA(B) receptor agonist and antagonist use d revealed that GABA(B) receptors are able to affect the development of the epileptic kindling state induced by pentylenetetrazole. (C) 2000 Elsevier Science Ltd. All rights reserved.