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Titolo:
THE EFFECTS OF AN INHIBITOR OF TRYPTOPHAN 2,3-DIOXYGENASE AND A COMBINED INHIBITOR OF TRYPTOPHAN 2,3-DIOXYGENASE AND 5-HT REUPTAKE IN THE RAT
Autore:
SALTER M; HAZELWOOD R; POGSON CI; IYER R; MADGE DJ; JONES HT; COOPER BR; COX RF; WANG CM; WIARD RP;
Indirizzi:
WELLCOME RES LABS,LANGLEY COURT BECKENHAM BR3 3BS KENT ENGLAND BURROUGHS WELLCOME CO RES TRIANGLE PK NC 27709
Titolo Testata:
Neuropharmacology
fascicolo: 2, volume: 34, anno: 1995,
pagine: 217 - 227
SICI:
0028-3908(1995)34:2<217:TEOAIO>2.0.ZU;2-F
Fonte:
ISI
Lingua:
ENG
Soggetto:
INCREASES EXTRACELLULAR SEROTONIN; CENTRAL-NERVOUS-SYSTEM; DORSAL RAPHE NEURONS; 5-HYDROXYINDOLEACETIC ACID; NORADRENERGIC NEURONS; ANTIDEPRESSANT DRUGS; CEREBROSPINAL-FLUID; LIVER CELLS; DEPRESSION; METABOLISM;
Keywords:
TRYPTOPHAN 2,3-DIOXYGENASE (TDO); 5-HYDROXYTRYPTAMINE (5-HT) REUPTAKE; CEREBROSPINAL FLUID (CSF); DEPRESSION; ANXIETY; ANTIDEPRESSANTS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
59
Recensione:
Indirizzi per estratti:
Citazione:
M. Salter et al., "THE EFFECTS OF AN INHIBITOR OF TRYPTOPHAN 2,3-DIOXYGENASE AND A COMBINED INHIBITOR OF TRYPTOPHAN 2,3-DIOXYGENASE AND 5-HT REUPTAKE IN THE RAT", Neuropharmacology, 34(2), 1995, pp. 217-227

Abstract

The effects of a novel inhibitor 680C91 ((E)-6-fluoro-3-[2-(3-pyridyl)vinyl]-1H-indole) of the key enzyme of tryptophan catabolism tryptophan 2,3-dioxygenase (TDO), and a novel inhibitor 709W92 ((E)-6-fluoro-3-[2-(4-pyridyl)vinyl]-1H-indole) of both TDO and 5-hydroxytryptamine (5-HT) reuptake, were examined on tryptophan catabolism, cerebrospinal fluid (CSF) concentrations of tryptophan and 5-HT and serotonergic-mediated physiology and behaviour in the rat. The catabolism of L-[ring-2-C-14]tryptophan in vivo was completely inhibited by prior administration of 709W92. 709W92, but not 680C91, potentiated head-twitch produced by 5-hydroxytryptophan, prevented head-twitch and whole brain 5-HT depletion produced by p-chloroamphetamine and rapidly decreased dorsal raphe firing. Both 709W92 and 680C91 elevated CSF tryptophan by up to 260% of basal concentration. A maximally effective dose of 680C91 elevated a global measure of brain extracellular 5-HT (CSF 5-HT) to concentrations similar to those seen maximally after exogenous tryptophan administration (approx 170% of basal). Maximally effective doses of 709W92 increased CSF 5-HT to concentrations comparable to those seen aftertryptophan and 5-HT reuptake inhibitor coadministration (approx 900% of basal) and to concentrations greater than those achieved maximally with serotonergically active antidepressant monotherapy (approx 500% of basal). 709W92 did not elevate CSF 5-HT to concentrations associatedwith the serotonin syndrome (approx 3000% of basal). The combined TDOinhibitor/5-HT reuptake inhibitor, 709W92, showed anxiolytic activityin the rat-pup vocalization model of anxiety. These results show that709W92 (a novel inhibitor of both TDO and 5-HT reuptake), can producean elevation of CSF 5-HT similar to that achieved with a serotonin reuptake inhibitor/tryptophan combination therapy but with a more sustained timecourse; such compounds may therefore have superior antidepressant efficacy in the clinic.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 29/02/20 alle ore 13:20:47