Tolerance and withdrawal to anticonvulsant action of clonazepam: Role of nitric oxide

The use of clonazepam in the long-term treatment of epilepsy is greatly inh ibited by its capacity to induce tolerance and dependence. A means of preve nting or minimizing the tolerance and dependence inducing properties is req uired. Here the role of nitric oxide in preventing the development of toler ance and withdrawal hyperexcitability was studied. In Wistar mrs, clonazepa m at a dose of 0.25 mg/kg i.p. twice daily produced tolerance to its antico nvulsant action in 28 days. After sudden cessation of therapy it produced h yperexcitability. Tolerance was shown by a decrease in seizure threshold to near control value while withdrawal hyperexcitability was evidenced by a s ignificant decrease in seizure threshold below the control value. L-Arginin e (a donor of nitric oxide) and N-omega-nitro-L-arginine (an inhibitor of n itric oxide synthase) were given in doses of 150 mg/kg and 8 mg/kg, respect ively on day 1, 3, 7, 14, 21 and 28 with clonazepam. Withdrawal hyperexcita bility was seen on day 1, 2 and 4 after cessation of drug therapy. Electros hock was used as a model of epilepsy and seizure thresholds were determined by an up and down method of Kimball et al. L-Arginine was found to inhibit the development tolerance as well as withdrawal hyperexcitability when adm inistered with clonazepam while Nm-L-arginine did not prevent either the de velopment of tolerance or withdrawal hyperexcitability in the electroshock model. In the PTZ model, however L-arginine had no effect on the anticonvul sant action and withdrawal hyperexcitability while inhibition of nitric oxi de synthesis prevented withdrawal hyperexcitability in PTZ-induced seizures . (C)2000 Prous Science. All rights reserved.