EFFECTS OF GABA(B) RECEPTOR ANTAGONISM ON THE DEVELOPMENT OF PENTYLENETETRAZOL-INDUCED KINDLING IN MICE

Pentylenetetrazol (PTZ) administered chronically in rodents induces ki ndling 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 pentylenetetra zol kindling. Naunyn-Schmiedeberg's Arch. Pharmacol, 349 (1994) 429-49 6]. Since GABA(B) receptor antagonism has been shown to improve cognit ive performance in rodents and primates we have examined the effects o f 3 antagonists: CGP 36742 (3-amino-propyl-n-butyl-phosphinic acid), C GP 56433 ([3-{1-(S)-[{3-(cyclohexylmethyl) osphinyl]-2-(S)-hydroxyprop yl]-amino]ethyl]benzoic acid) and CGP 61334 l)hydroxyphosphinyl]-propy l]-amino}methyl]-benzoic acid) on the induction of PTZ kindling in mic e 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) rec eptor autoradiography was performed on brain sections from these anima ls. Seizure intensity increased progressively in control mice reaching by 8 weeks a mean score which corresponded to clonic seizures. The GA BA(B) antagonists suppressed kindling during the first 4 weeks and aft er that restored the seizure intensity to the level of control animals . The level of kindling was proportional to the avoidance score. The d ensity 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.