Sensitisation to repeated withdrawal, in mice treated chronically with diazepam, is blocked by an NMDA receptor antagonist.

Mice were treated either with diazepam (15 mg/kg s.c. in oil), for 21 days, or for 3x7-day periods interspersed with two 72-h drug-free periods. Convulsant thresholds to pentylentetrazole infused into the tail vein 72 h following the final chronic treatment were lower in multiple-withdrawal mice than in mice which had experienced the same drug load, but only a single withdrawal, consistent with sensitisation of withdrawal events following previous withdrawal experience. The increase in seizure sensitivity of repeatedly withdrawn mice was prevented by treatment with the NMDA receptor antagonist CGP 39551 (20 mg/kg, i.p.) given once daily during the 3-day breaks in diazepam treatment, suggesting a role of glutamatergic transmission in the sensitisation process.