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 benzodiazepine (BZ) and indoleamine agonists in the rat striatum were investigated. 2 A biphasic inhibition of forskolin‐stimulated AC activity by the peripheral‐type agonist, Ro5‐4864, and a multiphasic inhibition by the non‐selective BZ, diazepam, was observed. One phase of AC inhibition is consistent with a G i ‐coupled receptor‐mediated action, whereas the other phases appear to involve a direct effect on the enzyme itself. 3 While the central‐type antagonist, flumazenil, had no effect on the ability of Ro5‐4864 to inhibit AC activity, the peripheral‐type receptor ligand, PK 11195, abolished the first phase of inhibition. 4 PK 11195 and pertussis toxin were found to block the inhibitory effect of various BZs and the indoleamines, melatonin and 2‐iodomelatonin, on induced AC activity. 5 Saturation binding studies, conducted at 30°C with [ 3 H]‐diazepam revealed a single binding site in the rat striatum ( K D = 19.3 ± 0.80 nM) which significantly decreased in 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 the presence of G i ‐coupled BZ receptors in the rat striatum. Thus, suppression of cyclic AMP production may contribute to the diverse neuropharmacological effects of BZs, melatonin and related drugs.