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 inhibited by its capacity to induce tolerance and dependence. A means of preventing or minimizing the tolerance and dependence inducing properties is required. Here the role of nitric oxide in preventing the development of tolerance and withdrawal hyperexcitability was studied. In Wistar rats, clonazepam at a dose of 0.25 mg/kg i.p. twice daily produced tolerance to its anticonvulsant action in 28 days. After sudden cessation of therapy it produced hyperexcitability. Tolerance was shown by a decrease in seizure threshold to near control value while withdrawal hyperexcitability was evidenced by a significant decrease in seizure threshold below the control value. L-Arginine (a donor of nitric oxide) and N omega-nitro-L-arginine (an inhibitor of nitric oxide synthase) were given in doses of 150 mg/kg and 8 mg/kg, respectively on day 1, 3, 7, 14, 21 and 28 with clonazepam. Withdrawal hyperexcitability was seen on day 1, 2 and 4 after cessation of drug therapy. Electroshock 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 administered with clonazepam while N omega-L-arginine did not prevent either the development of tolerance or withdrawal hyperexcitability in the electroshock model. In the PTZ model, however, L-arginine had no effect on the anticonvulsant action and withdrawal hyperexcitability while inhibition of nitric oxide synthesis prevented withdrawal hyperexcitability in PTZ-induced seizures.
Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
N
N
Gupta
V K
VK
Bhargava
P
P
Pandhi
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002998:Clonazepam / Q000494:pharmacology*; D004361:Drug Tolerance; D005260:Female; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D019335:Nitroarginine / Q000494:pharmacology; D010433:Pentylenetetrazole; D051381:Rats; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology; D013375:Substance Withdrawal Syndrome / Q000209:etiology*
D000927:Anticonvulsants; D018079:Receptors, GABA; D016194:Receptors, N-Methyl-D-Aspartate; D019335:Nitroarginine; D009569:Nitric Oxide; D002998:Clonazepam; D010433:Pentylenetetrazole