Selective changes in the in vivo effects of benzodiazepine receptor ligands after chemical kindling with FG 7142.

It has recently been demonstrated that kindling occurs with repeated administration of the benzodiazepine "inverse agonist" FG 7142. The present study was an investigation of the effects of other ligands for the benzodiazepine receptor in mice kindled with FG 7142. It was shown that over a range of doses the lowering effects of FG 7142 on the seizure threshold were greater in kindled animals than in control. In contrast, the hypothermic effect of FG 7142 was unaltered. The effects of the partial inverse agonist CGS 8216 were unaltered. The effects of the full inverse agonist DMCM were unchanged except for an enhancement of its convulsant effect when infused at a concentration of 100 mu gm 1-1. Studies with the full agonist benzodiazepine, flurazepam and the full agonist beta-carboline, ZK 93423, showed small but significant reductions in their hypothermic effects. The sedative and anticonvulsant effects of flurazepam were unaltered, whereas the anticonvulsant effects of ZK 93423 were decreased in animals kindled with FG 7142. There was a pronounced reduction in the anticonvulsant and hypothermic effects of the partial agonist beta-carboline, ZK 91296. These data do not fit any simple explanation of kindling being due to a change in the function of benzodiazepine receptors, although they may offer some support for the idea that kindling with FG 7142 produces a change in the effects of all beta-carboline compounds which act at the benzodiazepine receptor.