Effects of GABAB receptor antagonism on the development of Pentylenetetrazol-induced kindling in mice

Pentylenetetrazol (PTZ) administered chronically in rodents induces kindling which is considered to be a model of chronic epilepsy mediated through a specific interaction with the GABA-gated chloride ionophore. PTZ kindling also impairs shuttle-box learning indicating a possible modulation of memory storage [A. Becker, G. Grecksch, H. Mathies. The influence of diazepam on learning processes impaired by pentylenetetrazol kindling. Naunyn-Schmiedeberg's Arch. Pharmacol, 349 (1994) 429-496]. Since GABA(B) receptor antagonism has been shown to improve cognitive performance in rodents and primates we have examined the effects of 3 antagonists: CGP 36742 (3-amino-propyl-n-butyl-phosphinic acid), CGP 56433 ([3-{1-(S)-[{3-(cyclohexylmethyl) hydroxyphosphinyl]-2-(S)-hydroxypropyl]-amino]ethyl]benzoic acid) and CGP 61334 ([3-{[3[(diethoxymethyl)hydroxyphosphinyl]-propyl]-amino}methyl]-benzoic acid) on the induction of PTZ kindling in mice at 48 h intervals for 8 weeks. Subsequently the mice were tested in an active avoidance paradigm. At the end of the experiment GABA(B) receptor autoradiography was performed on brain sections from these animals. Seizure intensity increased progressively in control mice reaching by 8 weeks a mean score which corresponded to clonic seizures. The GABA(B) antagonists suppressed kindling during the first 4 weeks and after that restored the seizure intensity to the level of control animals. The level of kindling was proportional to the avoidance score. The density of GABA(B) receptor binding in brain sections from PTZ kindled mice was significantly greater than in controls. This was not altered by pretreatment with the GABA(B) antagonists except in the cerebellum. (C) 1998 Elsevier Science B.V. All rights reserved.