Cerebellar cyclic GMP and behavioral effects after acute and repeated administration of benzodiazepines in mice

The previous finding that benzodiazepine-induced changes in cyclic GMP in the cerebellum were poorly correlated with the impairment of motor function has now been extended further. The effects following acute, and during repeated administration of diazepam, quazepam and flurazepam were studied in mice. A 10 day period of daily treatment with 5 mg/kg p.o. was used in these studies. The content of cGMP was significantly reduced (P less than 0.05) during the chronic administration of quazepam and flurazepam except after 10 days for flurazepam. After diazepam, cGMP levels were lower than in control animals but a significant difference was observed only at the sixth and tenth day because a minimal threshold dose was used. Antagonism of pentylenetetrazol-induced convulsions was significantly (P less than 0.05) effective over the 10 day treatment for all drugs. Spontaneous motor activity was reduced by quazepam given for two days and by diazepam given for one day while this measure was unaffected by flurazepam given at the same dose which was effective in the other tests. These results further supported a lack of association between changes of cGMP content in the cerebellum and sedative or muscle relaxant effects of benzodiazepines, whereas the lowering of cGMP levels seemed to parallel effects that are not subject to tolerance such as the antagonism of pentylenetetrazol-induced convulsions.