ANTICONVULSANT EFFICACY OF ADCI (5-AMINOCARBONYL-LO,11-DIHYDRO-5H-DIBENZO[A,D] CYCLOHEPTEN-5,10-IMINE) AFTER ACUTE AND CHRONIC DOSING IN MICE

ADCI 11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine), a low-affinity uncompetitive N-methyl-D-aspartate (NMDA) antagonist, is a broad-spec trum anticonvulsant with a favorable side-effect profile. In the prese nt study, we sought to determine if tolerance develops to the anticonv ulsant activity of ADCI, using the maximal electroshock (MES) test to assess seizure protection. Mice were treated with three daily injectio ns of a 2 x ED(50) dose for MES protection (18 mg/kg, intraperitoneall y, i.p.) or vehicle for 7 or 14 days. On the day after the chronic tre atment protocol, all animals received a challenge dose of ADCI (18 mg/ kg) and 15 min later were evaluated in the MES test. In control animal s, 83-94% of animals were protected and the ADCI plasma levels immedia tely after the MES test were 5.5-9.7 mu g/ml. In treated animals, 29 a nd 0% of animals were protected at 7 and 14 days, respectively, and th e ADCI plasma levels were 77 and 52% of the control values, [H-3]Dizoc ilpine binding to brain NMDA receptors was unaltered by the chronic dr ug treatment. In subsequent experiments, we determined that 14-day chr onically treated animals could be completely protected by increased do ses of ADCI (ED(50) 28.9 mg/kg). In both naive and chronically treated animals receiving a challenge dose of ADCI, plasma drug levels decrea sed in two phases, the first with a time constant of similar to 55 min and the second with a much slower rate. The estimated plasma concentr ations of ADCI reflecting threshold (3-5 mu g/ml) and 50% protection ( 5-7.5 mu g/mg) were similar in naive and chronic animals. We conclude that tolerance to ADCI is due to pharmacokinetic factors (enhanced fir st-pass metabolism) and does not result from a reduction in anticonvul sant efficacy.