PK-11195 BLOCKADE OF BENZODIAZEPINE-INDUCED INHIBITION OF FORSKOLIN-STIMULATED ADENYLATE-CYCLASE ACTIVITY IN THE STRIATUM

1 The effects of benzodiazepine receptor antagonists on the inhibition of forskolin-stimulated adenylate cyclase (AC) activity by various be nzodiazepine (BZ) and indoleamine agonists in the rat striatum were in vestigated. 2 A biphasic inhibition of forskolin-stimulated AC activit y by the peripheral-type agonist, Ro5-4864, and a multiphasic inhibiti on by the non-selective BZ, diazepam, was observed. One phase of AC in hibition is consistent with a G(i)-coupled receptor-mediated action, w hereas the other phases appear to involve a direct effect on the enzym e itself. 3 While the central-type antagonist, flumazenil, had no effe ct on the ability of Ro5-4864 to inhibit AC activity, the peripheral-t ype receptor ligand, PK 11195, abolished the first phase of inhibition . 4 PK 11195 and pertussis toxin were found to block the inhibitory ef fect of various BZs and the indoleamines, melatonin and 2-iodomelatoni n, on induced AC activity. 5 Saturation binding studies, conducted at 30 degrees C with [H-3]-diazepam revealed a single binding site in the rat striatum (K-D = 19.3 +/- 0.80 nM) which significantly decreased i n affinity in the presence of GTP (K-D = 30.5 +/- 2.6 nM; P<0.05). No significant change in B-max was observed. 6 These findings indicate th e presence of G(i)-coupled BZ receptors in the rat striatum. Thus, sup pression of cyclic AMP production may contribute to the diverse neurop harmacological effects of BZs, melatonin and related drugs.