Diazepam attenuation of somatostatin binding and effect of somatostatin onaccumulation of inositol 1,4,5-trisphosphate in the rat frontoparietal cortex

Numerous reports in both humans and animals have confirmed that bezodiazepi nes produce amnesia; however, mechanisms mediating this effect are not clea r. In view of the important role of brain somatostatin (SRIF) in the cognit ive function of rats, this study sought to determine if the benzodiazepine, diazepam, alters somatostatinergic system in the rat frontoparietal cortex . Intraperitoneal (IP) administration of diazepam (5 mg/kg/day) to male Wis tar rats (200-250 g) for 3 or 7 days decreased the number of SRIF receptors (26 and 37%, respectively) in synaptosomes from the frontoparietal cortex, without influencing their apparent affinity. This decrease in the tracer b inding was not attributable to a direct effect of diazepam on SRIF receptor s, because no decrease of SRIF binding was induced by a large concentration of diazepam (10(-4) M) when the drug was added to a preparation of synapto somes fron frontoparietal cortex of untreated rats. To determine if the eff ect of diazepam on SRIF binding is related to the binding of diazepam to it s recognition site on the GABA(A) receptor, a benzodiazepine antagonist, 2- phenylpyrazolo[3,4-c]quinolin-3(5H)-one (CGS 8216) was administered before the diazepam injection. Pretreatment with CGS 8216 (20 mg/kg/day, IP) block ed completely the diazepam-induced decreased in the number of SRIF receptor s. CGS 8216 alone had no observable effect. The decrease in the number of I -125-Tyr(11)-SRIF receptors induced by diazepam was accompanied by a decrea se in the effect of SRIF, after 15 seconds of stimulation, on inositol 1,4, 5-trisphosphate (IP3) mass accumulation in the rat frontoparietal cortex at 3 (64%) or 7 days (59%) after its administration. Diazepam alone had no ob servable effect on mass accumulation of IP3. After 14 days of daily diazepa m injections, the levels of binding of I-125-Tyr(11)-SRIF in the frontopari etal cortex returned to control values, coinciding with the tolerance that develops to this benzodiazepine agonists when administered chronically. The decrease in IP3 levels was still observed after 14 days (57%) diazepam adm inistration. Diazepam and CGS 8216 did not affect SRIF-like immunoreactivit y levels in the frontoparietal cortex at the three time intervals studied ( 3, 7 or 14 days). The alteration of frontoparietal cortex SRIF receptor-eff ector system after 3 or 7 days of diazepam treatment suggests that somatost atinergic neurotransmission plays a role in the mechanism of diazepam actio n on memory. (C) 2000 American College of Neuropsychopharmocology. Publishe d by Elsevier Science Inc. All rights reserved.