![]() ![]() NMDA Nr1 neo−/− mice have been shown to display impairment in habituation, sensorimotor gating, and social behavior ( Duncan et al, 2006 Fradley et al, 2005 Mohn et al, 1999). Moreover, mice expressing only 5 to 10% of normal levels of the Nr1 subunit of the N-methyl- D-aspartate (NMDA) receptor (NMDA Nr1 neo−/−), thus mimicking a hypo-glutamatergic state, have been shown to exhibit behavioral abnormalities, which closely resemble those observed following NMDA receptor blockade by pharmacological means ( Mohn et al, 1999 Duncan et al, 2006 Boulay et al, 2007). Moderate doses of glutamate-NMDA receptor antagonists, such as phencyclidine, ketamine or MK-801 induce abnormal behaviors in rodents, including hyperactivity, stereotyped behaviors, altered social behavior, and deficits in sensory gating and cognition, all reminiscent of schizophrenic symptoms ( Lipska and Weinberger, 2000). These models are generally based on the widely accepted theory that a hyper-dopaminergic state along with a hypo-glutamatergic state underly the schizophrenic symptoms ( Carlsson, 1988 Gao et al, 2000). Locomotor hyperactivity induced by psychotomimetic agents in rodents or naturally observed in several transgenic mice have been claimed to model certain aspects of disorganized behavior, including agitation which belongs to the large cluster of positive symptoms ( Gainetdinov et al, 2001 Miyakawa et al, 1996). Pharmacological, neuro-developmental, neuro-toxic or transgenic approaches have been proposed in animal studies to reproduce behavioral alterations, which are reminiscent of some key symptoms of schizophrenia ( Gray et al, 2009 Lipska and Weinberger, 2000 Mohn et al, 1999). Schizophrenia is a severe mental illness that affects about 1% of the population, characterized by a constellation of positive, cognitive and negative symptoms ( Barnes et al, 1989 Andreasen, 1990). Together these findings show that the GlyT1 inhibitor, SSR103800, produces antipsychotic-like effects, which differ from those observed with compounds primarily targeting the dopaminergic system, and has a reduced side-effect potential as compared with these latter drugs. However, unlike these latter, SSR103800 did not produce catalepsy (retention on the bar test) up to 30 mg/kg p.o. ![]() Importantly, both classical (haloperidol) and atypical (olanzapine, clozapine and aripiprazole) antipsychotics were effective in all these models of hyperactivity. In contrast, SSR103800 failed to affect hyperactivity induced by amphetamine or naturally observed in dopamine transporter (DAT −/−) knockout mice (10–30 mg/kg p.o.). Results showed that SSR103800 (10–30 mg/kg p.o.) blocked hyperactivity induced by the non-competitive NMDA receptor antagonist, MK-801 and partially reversed spontaneous hyperactivity of NMDA Nr1 neo−/− mice. This study aimed at investigating the potential antipsychotic-like properties of SSR103800, with a particular focus on models of hyperactivity, involving either drug challenge (ie, amphetamine and MK-801) or transgenic mice (ie, NMDA Nr1 neo−/− and DAT −/−). Among them are glycine transporter-1 (GlyT1) inhibitors such as SSR103800, which indirectly enhance NMDA receptor function by increasing the glycine (a co-agonist for the NMDA receptor) levels in the synapse. As a result, there is a growing interest in the development of pharmacological agents with potential antipsychotic properties that enhance the activity of the glutamatergic system via a modulation of the NMDA receptor. However, the observation that antagonists of the glutamate N-methyl- D-aspartate (NMDA) receptor produce schizophrenic-like symptoms in humans has led to the idea of a dysfunctioning of the glutamatergic system via its NMDA receptor. Schizophrenia has been initially associated with dysfunction in dopamine neurotransmission. ![]()
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