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Titolo:
MODULATION OF [S-35] TBPS BINDING BY LIGANDS WITH PREFERENTIAL AFFINITY FOR BENZODIAZEPINE BZ(1) SITES IN THE CEREBRAL-CORTEX OF NEWBORN AND ADULT-RATS
Autore:
GIORGI O; LECCA D; CANCEDDA E; SERRA GP; CORDA MG;
Indirizzi:
UNIV CAGLIARI,DEPT TOXICOL,VIALE POETTO 1 I-09126 CAGLIARI ITALY UNIV CAGLIARI,DEPT ANIM BIOL & ECOL I-09126 CAGLIARI ITALY
Titolo Testata:
European journal of pharmacology. Molecular pharmacology section
fascicolo: 1, volume: 290, anno: 1995,
pagine: 37 - 47
SICI:
0922-4106(1995)290:1<37:MO[TBB>2.0.ZU;2-T
Fonte:
ISI
Lingua:
ENG
Soggetto:
GAMMA-AMINOBUTYRIC-ACID; GABA-A RECEPTOR; SUBUNIT MESSENGER-RNAS; CENTRAL-NERVOUS-SYSTEM; RECOGNITION SITES; POSTNATAL-DEVELOPMENT; BRAIN; SUBTYPES; HETEROGENEITY; ENHANCEMENT;
Keywords:
GABA(A) RECEPTOR; BENZODIAZEPINE BZ(1) SITE; BENZODIAZEPINE BZ(2) SITE; [S-35] TBPS ([S-35]T-BUTYLBICYCLOPHOSPHOROTHIONATE) BINDING; ONTOGENY; FLUNITRAZEPAM; CL 218,872; ZOLPIDEM; CEREBRAL CORTEX, RAT;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
40
Recensione:
Indirizzi per estratti:
Citazione:
O. Giorgi et al., "MODULATION OF [S-35] TBPS BINDING BY LIGANDS WITH PREFERENTIAL AFFINITY FOR BENZODIAZEPINE BZ(1) SITES IN THE CEREBRAL-CORTEX OF NEWBORN AND ADULT-RATS", European journal of pharmacology. Molecular pharmacology section, 290(1), 1995, pp. 37-47

Abstract

The present study was designed to compare the allosteric coupling between the Cl- channel of the GABA, receptor and the different benzodiazepine recognition site subtypes (BZ sites) in the cerebral cortex of newborn (5-day-old) and adult rats (90-day-old). To this aim, we reexamined the heterogeneity of cortical GABA(A) receptors in self- and cross-competition binding experiments using [H-3]flunitrazepam and two ligands with higher affinity for benzodiazepine BZ(1) sites relative to benzodiazepine BZ(2) sites, the triazolopyridazine ethyl-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo [4,3-b] pyridazine (CL 218,872) and theimidazopyridine -methylphenyl)-imidazo[1,2-a]-pyridine-3-acetamide hemitartrate (zolpidem). Benzodiazepine BZ(1) sites accounted for 52% ofthe total number of binding sites in adult rats, but were not detected in newborn rats. On the other hand, two classes of benzodiazepine BZ(2) sites with high and low affinity for zolpidem were present in newborn and adult rats. These sites were designated as benzodiazepine BZ(2H) (high affinity for zolpidem, K-d similar to 150 nM) and benzodiazepine BZ(2L) (low affinity for zolpidem, K-d similar to 3000 nM). High densities of benzodiazepine BZ(2H) sites were measured in both newborn and adult rats (75% and 41% of the total number of [H-3]flunitrazepam binding sites, respectively), whereas benzodiazepine BZ(2L) sites accounted for 25% and 7% of the total number of cortical sites in neonatesand adults, respectively. Flunitrazepam, CL 218,872 and zolpidem inhibited in a concentration-dependent manner the binding of [S-35]t-butylbicyclophosphorothionate ([S-35]TBPS) to the convulsant site of cortical GABA, receptors in newborn and adult rats. The IC50 for flunitrazepam was about 3-fold greater in adults than in neonates. This rightwardshift in the concentration-response curve may be due to a decrease with age in the intrinsic efficacy of flunitrazepam. In contrast, CL 218,872 and zolpidem were 4-fold more potent at inhibiting [S-35]TBPS binding in adult rats relative to neonates. The different affinities of CL 218,872 and zolpidem for benzodiazepine BZ(1) and BZ(2) receptors may account, at least in part, for the age-related changes in their inhibitory potencies. These results demonstrate that benzodiazepine BZ(2) sites mediate the modulation of [S-35]TBPS binding by benzodiazepine recognition site ligands in the cerebral cortex of newborn rats. Further, benzodiazepine BZ(2) sites may be involved in the inhibition of [S-35]TBPS binding by flunitrazepam, CL 218,872 and zolpidem in the cerebral cortex of adult rats.

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Documento generato il 02/04/20 alle ore 21:49:48