Role of cGMP in the mechanism of anxiolytic activity of U-78875

Abstract

The inhibition constant (K i) of U-78875 was investigated without and with mus incubation medium using in vitro ( 3H)-flunitrazepam [( 3H)-FNZ] binding to coritical membrane preparation. Also, the effect of U-78875 on cerebellar cyclic 3′,5′-guanosine monophosphate (cGMP) was studied in control and stressed (electric footshock) mice. The K i of U-78875 was 1.56 nM for inhibition of ( 3H)-FNZ binding. The presence of muscimol (10 −5 M) had no significant effect on the K i of U-78875. U-78875 and diazepam significantly decreased cerebellar cGMP, and this effect was antagonized by flumazenil. Both U-78875 and diazepam dose-dependently antagonized electric footshock-induced increases in cGMP, and U-78875 was two orders of magnitude more potent in stressed animals as compared to control animals. These biochemical investigations indicate that U-78875 is an agonist of benzodiazepine receptors, and cGMP may mediate its anxiolytic activity.