Procognitive and antipsychotic efficacy of glycine transport 1 inhibitors (GlyT1) in acute and neurodevelopmental models of schizophrenia: latent inhibition studies in the rat.
BACKGROUND
SSR103800 and SSR504734 are novel glycine transport 1 (GlyT1) inhibitors with therapeutic potential for the treatment of schizophrenia.


OBJECTIVE
The present studies investigated the effects of GlyT1 inhibitors in acute pharmacological and neurodevelopmental models of schizophrenia using latent inhibition in the rat; these latent inhibition (LI) models are believed to be predictive for treatments of positive, negative, and cognitive aspects of schizophrenia.


METHODS
LI, the poorer conditioning to a previously irrelevant stimulus, was measured in a conditioned emotional response procedure in male rats. The effects of SSR103800 or SSR504734 (both at 1, 3, and 10 mg/kg, i.p.) were determined on amphetamine-induced disrupted LI, MK-801-induced abnormally persistent LI, and neurodevelopmentally induced abnormally persistent LI in adult animals that had been neonatally treated with a nitric oxide synthase inhibitor.


RESULTS
SSR103800 (1 and 3 mg/kg) and SSR504734 (1 and 10 mg/kg) potentiated LI under conditions where LI was not present in nontreated controls and SSR103800 (1 mg/kg) reversed amphetamine-induced disrupted LI while not affecting LI on its own. Additionally, SSR103800 (1 and 3 mg/kg) and SSR504734 (3 and 10 mg/kg) reversed abnormally persistent LI induced by MK-801. In the neurodevelopmental model, SSR504734 (3 and 10 mg/kg) reverted the LI back to control (normal) levels.


CONCLUSIONS
These preclinical data, from acute and neurodevelopmental models, suggest that GlyT1 inhibition may exhibit activity in the positive, negative, and cognitive symptom domains of schizophrenia.
Black
Mark D
MD
CNS Department, Sanofi-Aventis, 1041 Route 202/206, Bridgewater, NJ 08807, USA. mark.black@sanofi-aventis.com
Varty
Geoffrey B
GB
Arad
Michal
M
Barak
Segev
S
De Levie
Amaya
A
Boulay
Denis
D
Pichat
Philippe
P
Griebel
Guy
G
Weiner
Ina
I
D000375:Aging / Q000523:psychology*; D000661:Amphetamine / Q000037:antagonists & inhibitors / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000633:toxicity; D003071:Cognition / Q000187:drug effects*; D003216:Conditioning, Operant / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D019335:Nitroarginine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013216:Reflex, Startle / Q000187:drug effects*; D012559:Schizophrenia / Q000188:drug therapy*; D012565:Schizophrenic Psychology
C507205:2-chloro-N-((S)-phenyl((2S)-piperidin-2-yl)methyl)-3-trifluoromethyl benzamide; D014150:Antipsychotic Agents; D001549:Benzamides; D000697:Central Nervous System Stimulants; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D050487:Glycine Plasma Membrane Transport Proteins; D010880:Piperidines; D019335:Nitroarginine; D016291:Dizocilpine Maleate; D000661:Amphetamine; D006220:Haloperidol