Acute and chronic effects of the benzodiazepine receptor ligand FG 7142: proconvulsant properties and kindling

Abstract

1 The effects of the acute and chronic administration of the β-carboline benzodiazepine receptor ligand, FG 7142 were studied in mice. 2 On acute administration FG7142 (at doses between 10 and 40 mgkg⁻¹) lowered seizure thresholds to infused pentylenetetrazol (PTZ) but showed an unusual dose-response curve in that higher doses had less effect. The duration of action was considerably longer than that of other β-carbolines, such as ethyl-β-carboline-3-carboxylate (βCCE). 3 During repeated administration, doses of FG7142 which were initially proconvulsant subsequently produced generalized seizures on average in 60% of animals after 12 once daily treatments. This seemed to be a form of chemical kindling. 4 The effects of different drug administration regimes were studied. Once daily dosage was shown to be the optimum for kindling production, and was therefore used for subsequent experiments. 5 Kindling lasted for at least one month after 12 single once daily doses of 40 mgkg⁻¹ (FG 7142). 6 The administration of the benzodiazepine antagonist Ro 15–1788 concurrent with FG7142 prevented kindling. When Ro 15–1788 was given to kindled animals along with a challenge dose of FG7142, it prevented the expression of kindled seizures. These data show that kindling is mediated via the benzodiazepine receptor.