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Titolo:
Coadministration of 5-hydroxytryptamine(1A) antagonist WAY-100635 preventsfluoxetine-induced desensitization of postsynaptic 5-hydroxytryptamine(1A)receptors in hypothalamus
Autore:
Serres, F; Muma, NA; Raap, DK; Garcia, F; Battaglia, G; Van de Kar, LD;
Indirizzi:
Loyola Univ, Stritch Sch Med, Dept Pharmacol, Maywood, IL 60153 USA LoyolaUniv Maywood IL USA 60153 d, Dept Pharmacol, Maywood, IL 60153 USA
Titolo Testata:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
fascicolo: 1, volume: 294, anno: 2000,
pagine: 296 - 301
SICI:
0022-3565(200007)294:1<296:CO5AWP>2.0.ZU;2-8
Fonte:
ISI
Lingua:
ENG
Soggetto:
PLACEBO-CONTROLLED TRIAL; IN-VIVO MICRODIALYSIS; LONG-TERM FLUOXETINE; NEUROENDOCRINE RESPONSES; 5-HT1A RECEPTORS; ANTIDEPRESSANT DRUGS; MAJOR DEPRESSION; G(O) PROTEINS; DOUBLE-BLIND; PAROXETINE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
32
Recensione:
Indirizzi per estratti:
Indirizzo: Van de Kar, LD Loyola Univ, Stritch Sch Med, Dept Pharmacol, 2160 S 1st Ave, Maywood, IL 60153 USA Loyola Univ 2160 S 1st Ave Maywood IL USA 60153 L 60153 USA
Citazione:
F. Serres et al., "Coadministration of 5-hydroxytryptamine(1A) antagonist WAY-100635 preventsfluoxetine-induced desensitization of postsynaptic 5-hydroxytryptamine(1A)receptors in hypothalamus", J PHARM EXP, 294(1), 2000, pp. 296-301

Abstract

Treatment with selective serotonin reuptake inhibitors induces a desensitization of hypothalamic postsynaptic 5-hydroxytryptamine (5-HT)(1A) receptors in humans and rats. This study investigated whether fluoxetine-induced desensitization is due to overactivation of postsynaptic 5-HT1A receptors; whether blockade of somatodendritic 5-HT1A autoreceptors accelerates this desensitization; and whether desensitization is associated with a reduction ofGz proteins, which couple to 5-HT1A receptors. WAY-100635 was tested at low doses (0.03-0.3 mg/kg), which antagonize somatodendritic 5-HT1A autoreceptors in the raphe nuclei, and at a higher dose (1 mg/kg), which completely blocks postsynaptic 5-HT1A receptors. Plasma levels of oxytocin and adrenalcorticotrophic hormone (corticotropin) were measured as peripheral indicators of hypothalamic 5-HT1A receptor function. Daily injections of fluoxetine (10 mg/kg/day i.p.) for 2 days did not desensitize 5-HT1A receptors but three daily injections of fluoxetine produced a partial desensitization of the hormone responses to (+/-)-8-hydroxy-2-dipropylaminoetetralin (50 mu g/kg s.c.). WAY-100635 (0.03-0.3 mg/kg) did not accelerate or potentiate the fluoxetine-induced desensitization of 5-HT1A receptors. However, WAY-100635 at a dose that completely blocks postsynaptic 5-HT1A receptors (1.0 mg/kg) completely prevented the fluoxetine-induced desensitization of 5-HT1A receptors. These data demonstrate that at least 3 days of fluoxetine exposure isrequired to produce a homologous desensitization of hypothalamic 5-HT1A receptors. Although previous studies indicate that injections of fluoxetine for 14 days produce a reduction of Gz protein levels in the hypothalamus, the levels of Gz proteins were not affected by either fluoxetine or WAY-100635. Alternative mechanisms mediating the initial stages of 5-HT1A receptor desensitization could involve post-translational modifications in the 5-HT1Areceptor-Gz protein-signaling cascade.

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Documento generato il 01/04/20 alle ore 11:16:20