Characterization of SSR103800, a selective inhibitor of the glycine transporter-1 in models predictive of therapeutic activity in schizophrenia.
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.
Boulay
Denis
D
Sanofi-Aventis, CNS Department, 31 avenue Paul Vaillant Couturier, Bagneux, France. denis.boulay@sanofi-aventis.com
Pichat
Philippe
P
Dargazanli
Gihad
G
Estenne-Bouhtou
Genevieve
G
Terranova
Jean Paul
JP
Rogacki
Nancy
N
Stemmelin
Jeanne
J
Coste
Annick
A
Lanneau
Christophe
C
Desvignes
Christophe
C
Cohen
Caroline
C
Alonso
Richard
R
Vigé
Xavier
X
Biton
Bruno
B
Steinberg
Régis
R
Sevrin
Mireille
M
Oury-Donat
Florence
F
George
Pascal
P
Bergis
Olivier
O
Griebel
Guy
G
Avenet
Patrick
P
Scatton
Bernard
B
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
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