title: Characterization of SSR103800, a selective inhibitor of the glycine transporter-1 in models predictive of therapeutic activity in schizophrenia.
abstract: 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.
authors.affiliation: Sanofi-Aventis, CNS Department, 31 avenue Paul Vaillant Couturier, Bagneux, France. denis.boulay@sanofi-aventis.com
authors.forename: Denis
authors.initials: D
authors.lastname: Boulay
authors.forename: Philippe
authors.initials: P
authors.lastname: Pichat
authors.forename: Gihad
authors.initials: G
authors.lastname: Dargazanli
authors.forename: Genevieve
authors.initials: G
authors.lastname: Estenne-Bouhtou
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Terranova
authors.forename: Nancy
authors.initials: N
authors.lastname: Rogacki
authors.forename: Jeanne
authors.initials: J
authors.lastname: Stemmelin
authors.forename: Annick
authors.initials: A
authors.lastname: Coste
authors.forename: Christophe
authors.initials: C
authors.lastname: Lanneau
authors.forename: Christophe
authors.initials: C
authors.lastname: Desvignes
authors.forename: Caroline
authors.initials: C
authors.lastname: Cohen
authors.forename: Richard
authors.initials: R
authors.lastname: Alonso
authors.forename: Xavier
authors.initials: X
authors.lastname: Vigé
authors.forename: Bruno
authors.initials: B
authors.lastname: Biton
authors.forename: Régis
authors.initials: R
authors.lastname: Steinberg
authors.forename: Mireille
authors.initials: M
authors.lastname: Sevrin
authors.forename: Florence
authors.initials: F
authors.lastname: Oury-Donat
authors.forename: Pascal
authors.initials: P
authors.lastname: George
authors.forename: Olivier
authors.initials: O
authors.lastname: Bergis
authors.forename: Guy
authors.initials: G
authors.lastname: Griebel
authors.forename: Patrick
authors.initials: P
authors.lastname: Avenet
authors.forename: Bernard
authors.initials: B
authors.lastname: Scatton
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology*; D004192:Discrimination, Psychological / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005849:Gerbillinae; D005998:Glycine / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D016202:N-Methylaspartate / Q000502:physiology; D010622:Phencyclidine / Q000494:pharmacology; D021641:Recognition, Psychology / Q000187:drug effects; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy*; D013237:Stereoisomerism; D013550:Swimming / Q000523:psychology
chemical_list: D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D050487:Glycine Plasma Membrane Transport Proteins; C493267:Slc6a9 protein, mouse; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D010622:Phencyclidine; D005998:Glycine