Diazepam attenuation of somatostatin binding and effect of somatostatin on accumulation of inositol 1,4,5-trisphosphate in the rat frontoparietal cortex.
Numerous reports in both humans and animals have confirmed that benzodiazepines produce amnesia; however, mechanisms mediating this effect are not clear. In view of the important role of brain somatostatin (SRIF) in the cognitive function of rats, this study sought to determine if the benzodiazepine, diazepam, alters somatostatinergic system in the rat frontoparietal cortex. Intraperitoneal (i.p.) administration of diazepam (5 mg/kg/day) to male Wistar 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 binding was not attributable to a direct effect of diazepam on SRIF receptors, 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 synaptosomes from frontoparietal cortex of untreated rats. To determine if the effect of diazepam on SRIF binding is related to the binding of diazepam to its 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, i.p.) blocked completely the diazepam-induced decrease in the number of SRIF receptors. CGS 8216 alone had no observable effect. The decrease in the number of 125I-Tyr11-SRIF receptor induced by diazepam was accompanied by a decrease 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 observable effect on mass accumulation of IP3. After 14 days of daily diazepam injections, the levels of binding of 125I-Tyr11-SRIF in the frontoparietal 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 administration. Diazepam and CGS 8216 did not affect SRIF-like immunoreactivity levels in the frontoparietal cortex at the three time intervals studied (3, 7 or 14 days). The alteration of frontoparietal cortex SRIF receptor-effector system after 3 or 7 days of diazepam treatment suggests that somatostatinergic neurotransmission plays a role in the mechanism of diazepam action on memory.
Martínez-Ferrer
A
A
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Alcalá, Alcala de Henares, Madrid, Spain.
Boyano-Adánez
M C
MC
Izquierdo-Claros
R M
RM
Arilla-Ferreiro
E
E
D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D001667:Binding, Competitive / Q000187:drug effects; D003975:Diazepam / Q000008:administration & dosage* / Q000037:antagonists & inhibitors; D004334:Drug Administration Schedule; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism; D058787:GABA-A Receptor Antagonists; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D007457:Iodine Radioisotopes; D008297:Male; D010296:Parietal Lobe / Q000187:drug effects* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013004:Somatostatin / Q000378:metabolism* / Q000494:pharmacology; D013574:Synaptosomes / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism
D014151:Anti-Anxiety Agents; D058787:GABA-A Receptor Antagonists; D007457:Iodine Radioisotopes; D011720:Pyrazoles; D013004:Somatostatin; C033830:2-phenylpyrazolo(4,3-c)quinolin-3(5H)-one; D015544:Inositol 1,4,5-Trisphosphate; D010738:Type C Phospholipases; D003975:Diazepam