Epilepsia, zyxwvutsrqpon 36(6):56&571, 1995 zyxwvutsrqponm Raven Press, Ltd., New zyxwvutsrq York zyxwvutsrqp 6 International League Against Epilepsy zyxwvutsrqpo Anticonvulsant Efficacy of ADCI (5-Aminocarbonyl- 10,l l-dihydro-5H-dibenzo[a,dl cyclohepten-5,lO-imine) After Acute and Chronic Dosing in Mice Michael A. Rogawski, Dung Q. Le, “Duangchan Uyakul, “Lewis K. Pannell, Swaminathan Subramaniam, Shun-ichi Yamaguchi, and Tushar G. Kokate Neuronal Excitability Section, Epilepsy Research Branch, National Institute of Neurological Disorders and Stroke, and *Laboratory of Analytical Chemistry, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland, U.S.A. Summary: ADCI (5-aminocarbonyl-10,l I-dihydro-5H- dibenzo[a,d]cyclohepten-S,lO-imine), a low-affinity un- competitive N-methyl+-aspartate (NMDA) antagonist, is a broad-spectrum anticonvulsant with a favorable side- effect profile. In the present study, we sought to deter- mine if tolerance develops to the anticonvulsant activity of ADCI, using the maximal electroshock (MES) test to assess seizure protection. Mice were treated with three daily injections of a 2 zyxwvutsrq x ED,, dose for MES protection (18 mg/kg, intraperitoneally, i.p.) or vehicle for 7 or 14 days. On the day after the chronic treatment protocol, all animals received a challenge dose of ADCI (18 mg/kg) and 15 min later were evaluated in the MES test. In con- trol animals, 83-94% of animals were protected and the ADCI plasma levels immediately after the MES test were 5.5-9.7 yg/ml. In treated animals, 29 and 0% of animals were protected at 7 and 14 days, respectively, and the ADCI plasma levels were 77 and 52% of the control val- ues. [3H]Dizocilpine binding to brain NMDA receptors was unaltered by the chronic drug treatment. In subse- quent experiments, we determined that 14-day chroni- cally treated animals could be completely protected by increased doses of ADCI (ED,, 28.9 mg/kg). In both na- ive and chronically treated animals receiving a challenge dose of ADCI, plasma drug levels decreased in two phases, the first with a time constant of -55 min and the second with a much slower rate. The estimated plasma concentrations of ADCI reflecting threshold (3-5 pg/ml) and 50% protection (5-7.5 yg/mg) were similar in naive and chronic animals. We conclude that tolerance to ADCI is due to pharmacokinetic factors (enhanced first-pass metabolism) and does not result from a reduction in an- ticonvulsant efficacy. Key Words: Anticonvulsant drug- Tolerance-Mouse-Maximal electroshock test- [3H]Dizocilpine binding. Chronic administration of some anticonvulsant drugs leads to a progressive loss in their ability to protect against seizures, a phenomenon referred to as “tolerance” (1); e.g., during the initial weeks of therapy with carbamazepine (CBZ), blood levels decreased due to autoinduction of metabolism (2). This pharmacokinetic (metabolic) tolerance can be overcome by increasing the CBZ dose (3,4). For Received May 31, 1994; revision accepted September 13, 1994. Address correspondence and reprint requests to Dr. M. A. Rogawski at Neuronal Excitability Section, Epilepsy Research Branch, NINDS, NIH, Bldg. 10, Room 5C-205, Bethesda, MD 20892, U.S.A. Mr. Le’s present address is University of Maryland School of Medicine, 655 W. Baltimore St., Baltimore, MD 21201, U.S.A. Dr. Uyakul’s present address is Food Analysis Division, De- partment of Medical Sciences, Yodse, Bangkok 10100, Thailand. other anticonvulsant drugs, most notably benzodi- azepines (BZDs) (5-7), blood levels do not decrease with chronic therapy and the tolerance that devel- ops is due to a reduction in the biological activity of the drug. Because it may not be possible to over- come this type of tolerance by raising the dose, such pharmacodynamic (functional) tolerance may diminish the therapeutic utility of a drug. Investigators have reported the development of tolerance to certain behavioral actions of the un- competitive (channel blocking) N-methyl-D-as- partate (NMDA) antagonists phencyclidine (8,9) and dizocilpine (10,ll). However, whether all un- competitive NMDA antagonists induce tolerance and whether there is tolerance to the anticonvulsant activity (12) of this class of drugs has not been well studied. 566