Addictive Behavior & Dual Diagnosis

Methadone is widely used in preventation of opiate withdrawal and also treatment opiate addiction. In addition to its clinical uses some studies demonstrated that methadone is associated with some alterations in seizure susceptibility. In this study, we tried to clarify the modulatory effect of methadone in clonic seizure threshold (CST) induced by pentylenetetrazole (PTZ) in mice, and we also further determined the probability role of N-Methyl-D- Aspartate (NMDA) receptor or Nitric oxide (NO) signaling in tolerance, dependence and seizure threshold of methadone. Our data showed that methadone (0.1,0.3,1, and 3 mg/kg) in acute administration has pro convulsive effect whereas chronic injection ( 3mg/kg, 3times/day for 5 days) enhanced seizure threshold. The noneffective (i.e., did not significantly alter the PTZ-induced seizure threshold by itself) doses of NMDA receptor antagonists [Ketamine (0.5 mg/kg) and MK-801(0.05 mg/kg)] were able to inhibit the pro-convulsive effect of methadone, while the non-effective doses of a nonspecific NOS inhibitor [L-NAME (10 mg/kg)] and a specific nNOS inhibitor [7-NI(15mg/kg)] could reversed the anti-convulsive effect of methadone in chronic administration. Additionally, the withdrawal syndrome signs, precipitated by naloxone and also anti-nociception effects of methadone were reduced by administration of NMDA receptor antagonists and NOS inhibitors accompanying methadone. These results suggest the involvement of NMDA receptors in pro and NO pathway in anti-convulsive effects of acute and chronic administration of methadone respectively and also both of them in dependence and tolerance.