Catalogo Articoli (Spogli Riviste)

OPAC HELP

Titolo:
SUBTYPE SPECIFICITY OF GAMMA-AMINOBUTYRIC-ACID TYPE-A RECEPTOR ANTAGONISM BY CLOZAPINE
Autore:
KORPI ER; WONG G; LUDDENS H;
Indirizzi:
ALKO GRP LTD,CTR BIOMED RES,POB 350 SF-00101 HELSINKI FINLAND UNIV HEIDELBERG,CTR BIOL MOLEC,MOLEC NEUROENDOCRINOL LAB D-69120 HEIDELBERG GERMANY
Titolo Testata:
Naunyn-Schmiedeberg's archives of pharmacology
fascicolo: 4, volume: 352, anno: 1995,
pagine: 365 - 373
SICI:
0028-1298(1995)352:4<365:SSOGTR>2.0.ZU;2-W
Fonte:
ISI
Lingua:
ENG
Soggetto:
SUBUNIT MESSENGER-RNAS; RAT-BRAIN; GABA(A) RECEPTOR; BINDING-SITES; BENZODIAZEPINE; SCHIZOPHRENIA; PHARMACOLOGY; NEUROLEPTICS; DERIVATIVES; SEROTONIN;
Keywords:
CLOZAPINE; BRAIN REGIONAL HETEROGENEITY; GABA ANTAGONISTS; GABA(A) RECEPTOR SUBUNITS; RECOMBINANT RECEPTORS; [S-35] TBPS BINDING; [S-35] TBPS AUTORADIOGRAPHY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
55
Recensione:
Indirizzi per estratti:
Citazione:
E.R. Korpi et al., "SUBTYPE SPECIFICITY OF GAMMA-AMINOBUTYRIC-ACID TYPE-A RECEPTOR ANTAGONISM BY CLOZAPINE", Naunyn-Schmiedeberg's archives of pharmacology, 352(4), 1995, pp. 365-373

Abstract

Clozapine, an atypical neuroleptic, functionally antagonizes the gamma-aminobutyric acid-induced chloride uptake via the main central inhibitory receptor, gamma-aminobutyric acid type A (GABA(A)) receptor, in brain vesicles. GABA(A) antagonism by micromolar concentrations of clozapine is more efficient in rat cerebrocortical and hippocampal membranes than in cerebellar membranes, as evidenced by clozapine reversal GABA-inhibition of [S-35]t-butylbicydophosphorothionate ([S-35]TBPS) binding. A typical neuroleptic, haloperidol, failed to antagonize GABA in any of these brain regions, while the specific GABA(A) antagonist -2',3'-propyl)-3-amino-6-p-methoxyphenylpyrazinium bromide (SR 95531) was efficient in all three brain regions. Clozapine action on [S-35]TBPSbinding was unaffected by the benzodiazepine receptor antagonist flumazenil. Clozapine inhibited the binding of [H-3]muscimol and [H-3]SR 95531 to the GABA recognition site, but this effect only partially correlated with the regional differences in and the potency of clozapine antagonism of GABA-inhibition of [(35)]TBPS binding, suggesting that also other than GABA sites may mediate clozapine actions. Autoradiography of [S-35]TBPS binding revealed GABA antagonism by clozapine in most brain regions. Main exceptions were cerebellar granule cell and molecular layers, olfactory bulb external plexiform and glomerular layers and primary olfactory cortex, where clozapine antagonized GABA inhibition less than average, and lateral hypothalamic and preoptic areas whereits antagonism was greater than average. Recombinant alpha 6 beta 2 gamma 2 receptors, the predominant alpha 6 subunit-containing receptor subtype in cerebellar granule cells, failed to show GABA antagonism byclozapine up to 100 mu M. In contrast, recombinant alpha 1 beta 2 gamma 2 receptors, forming the predominant receptor subtype in the brain,were clozapine sensitive. Recombinant alpha 6 beta 2 gamma 2 and alpha 6 beta 3 gamma 2 receptors resulted in clozapine-insensitive receptors, whereas alpha 6 beta 1 gamma 2 receptors were clozapine sensitive. The efficacy of clozapine to antagonize GABA in alpha 1 beta x gamma 2 receptors decreased in the order of alpha 1 beta 1 gamma 2>alpha 1 beta 2 gamma 2>alpha 1 beta 3 gamma 2. The results indicate that clozapine antagonizes the function of most GABA(A) receptor subtypes, and that the interaction is determined by the interaction of the alpha and beta subunit variants. GABA antagonism is a unique property of clozapine, not shared by haloperidol, which might be involved in the pharmacological mechanism for the increased seizure susceptibility associated with clozapine treatment.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 31/03/20 alle ore 21:35:43