Characterization of SSR103800, a selective inhibitor of the glycine transporter-1 in models predictive of therapeutic activity in schizophrenia

被引：75

作者：

Boulay, Denis ^{[1
]}

Pichat, Philippe ^{[1
]}

Dargazanli, Gihad ^{[1
]}

Estenne-Bouhtou, Genevieve ^{[1
]}

Terranova, Jean Paul ^{[2
]}

Rogacki, Nancy ^{[3
]}

Stemmelin, Jeanne ^{[1
]}

Coste, Annick ^{[1
]}

Lanneau, Christophe ^{[1
]}

Desvignes, Christophe ^{[2
]}

Cohen, Caroline ^{[1
]}

Alonso, Richard ^{[2
]}

Vige, Xavier ^{[1
]}

Biton, Bruno ^{[1
]}

Steinberg, Regis ^{[2
]}

Sevrin, Mireille ^{[1
]}

Oury-Donat, Florence ^{[2
]}

George, Pascal ^{[1
]}

Bergis, Olivier ^{[1
]}

Griebel, Guy ^{[1
]}

Avenet, Patrick ^{[1
]}

Scatton, Bernard ^{[1
]}

机构：

[1] Sanofi Aventis, CNS Dept, F-92220 Bagneux, France

[2] Sanofi Aventis, Montpellier, France

[3] Sanofi Aventis, Bridgewater, NJ USA

来源：

PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR | 2008年 / 91卷 / 01期

关键词：

atypical antipsychotic; antidepressant; glycine; GlyT1; inhibitor; schizophrenia; SSR103800;

D O I：

10.1016/j.pbb.2008.06.009

中图分类号：

B84 [心理学]; C [社会科学总论]; Q98 [人类学];

学科分类号：

03 ; 0303 ; 030303 ; 04 ; 0402 ;

摘要：

On native human, rat and mouse glycine transporter-1 (GlyT1), SSR130800 behaves as a selective inhibitor with IC50 values of 1.9, 5.3 and 6.8 nM respectively. It reversibly blocked glycine uptake in mouse brain cortical homogenates, increased extracellular levels of glycine in the rat prefrontal cortex, and potentiated NMDA-mediated excitatory postsynaptic currents in rat hippocampal slices. SSR103800 (30 mg/kg, p.o.) decreased MK-801- and PCP-induced locomotor hyperactivity in rodents. SSR103800 (1 and 10 mg/kg, p.o.) attenuated social recognition deficit in adult rats induced by neonatal injections of PCP (10 mg/kg, s.c., on post-natal day 7, 9 and 11). SSR103800 (3 mg/kg, p.o.) counteracted the deficit in short-term visual episodic-like memory induced by a low challenge dose of PCP (1 mg/kg, i.p.), in PCP-sensitized rats (10 mg/kg, i.p.). SSR103800 (30 mg/kg, i.p.) increased the prepulse inhibition of the startle reflex in DBA/1J mice. SSR103800 decreased defensive- and despair-related behaviors in the tonic immobility test in gerbils (10 and 30 mg/kg, p.o.) and in the forced-swimming procedure in rats (1 and 3 mg/kg, p.o.), respectively. These findings suggest that SSR103800 may have a therapeutic potential in the management of the core symptoms of schizophrenia and comorbid depression states. (c) 2008 Elsevier Inc. All rights reserved.

引用

页码：47 / 58

页数：12

共 44 条

[21] The neuropsychopharmacology of phencyclidine: From NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia [J].