Lack of tolerance or withdrawal effects in mice after chronic administration of the non-sedating anxiolytic, CGS 9896.

CGS 9896, a non-sedating anxiolytic, was compared to diazepam with respect to the development of tolerance and withdrawal. Both compounds were administered daily to mice at various doses (3, 10 or 30 mg/kg) for periods of up to 4 weeks. Measures of sedation/muscle relaxation, motor activity and anticonvulsant effects were then assessed. When administered acutely, CGS 9896 increased motor activity, had no effect on traction reflex, and elevated the threshold for PTZ-induced convulsions. After chronic administration of CGS 9896, no changes in these parameters were observed compared to the effects seen after acute treatment. Acute administration of diazepam reduced motor activity, impaired traction reflex and increased PTZ-induced convulsion threshold. Tolerance developed to the effects of diazepam in all three measures. Following a four week dosing period with 30 mg/kg of either CGS 9896 or diazepam, the drugs were withdrawn and similar behavioral measures obtained at various withdrawal intervals up to 15 days. In separate groups of mice, precipitated withdrawal was also assessed by the administration of the benzodiazepine agonist, CGS 8216. No effects were observed after any period of withdrawal from CGS 9896. By contrast, withdrawal from diazepam resulted in significant alterations of motor activity and convulsion threshold. These results indicate that CGS 9896 is likely to be free of undesirable tolerance and withdrawal effects typically associated with the benzodiazepines.