Co-existence of kindling induced by the β-carboline, FG 7142, and tolerance to diazepam following chronic treatment in mice

Abstract

The effect of chronic treatment with the β-carboline, FG 7142, followed by chronic treatment with diazepam (DZP) on the acute effects of DZP and FG 7142 were studied. Mice were treated for 16 days with FG 7142 (40 mg/kg i.p.) followed by treatment with DZP (5 or 20 mg/kg i.p.) for 9 days. At the end of this period, the anticonvulsant, antipunishment and locomotor sedative properties of a test dose of DZP were assessed, as were the convulsant properties of FG 7142. During the chronic treatment with FG 7142, 80% of the mice developed clonic convulsions in response to the β-carboline, and this increased sensitivity to FG 7142 (kindling) remained following the chronic DZP treatment. Thus long-term treatment with DZP does not reverse the changes which occur during FG 7142-induced kindling. Chronic treatment with DZP for 9 days gave rise to tolerance to its pharmacological effects as assessed in the 4-plate test of antipunishment activity, in a test of locomotor sedation, and by its ability to increase the convulsant threshold of intravenously administered pentylenetetrazol. The development of tolerance to DZP was not affected by a prior chronic treatment with FG 7142. Nor were the acute effects induced by DZP altered by a prior chronic treatment with FG 7142. Apart from reducing its own convulsant threshold, chronic treatment with FG 7142 had no effect in any of the experiments. These results suggest that kindling induced by FG 7142 and tolerance to DZP depend on different mechanisms. In neither case were the pharmacological changes induced by chronic administration reflected by changes in the biochemical measures of the coupling between benzodiazepine binding sites and γ-aminobutyric acid (GABA) receptors.