Tolerance to and Withdrawal from Anticonvulsant Action of Diazepam: Role of Nitric Oxide

Abstract

Tolerance to the anticonvulsant action of diazepam as a result of central nervous system adaptation limits its use in epilepsy. In Wistar rats, diazepam 5 mg/kg ip twice daily produced tolerance to its anticonvulsant action in 6 days. Abrupt withdrawal caused hyperexcitability. Tolerance manifested as a decrease in seizure threshold to near-control values, while withdrawal hyperexcitability was evidenced by a significant decrease in seizure threshold below the control value. This effect was seen both in the “same group design” and “separate group design.” l-Arginine (a donor of nitric oxide) and Nω-nitro-l-arginine (an inhibitor of nitric oxide synthase) were given in doses of 150 and 8 mg/kg, respectively, on Days 1, 3, and 6 along with diazepam in the same group design. Their role in preventing the development of tolerance to the anticonvulsant effect was seen on Days 1, 3, and 6. Withdrawal hyperexcitability was seen on Days 1, 2, and 4 after cessation of drug therapy. Both electroshock and pentylenetetrazole (PTZ) infusion were used as models of epilepsy, and seizure thresholds were determined. The up and down method of A. W. Kimball, W. T. Burnett, and G. D. Doherty (Radiat Res 1957;7:1–12) was used to determine the seizure threshold in cases of electroshock-induced seizures. l-Arginine, when administered with diazepam, was found to inhibit tolerance as well as withdrawal hyperexcitability. Nω-nitro-l-arginine did not prevent the development of tolerance or withdrawal hyperexcitability in the electroshock model, while in the PTZ model inhibition of nitric synthesis prevented withdrawal hyperexcitability but had no effect on the development of tolerance.