The Glycine Transporter-1 Inhibitor SSR103800 Displays a Selective and Specific Antipsychotic-like Profile in Normal and Transgenic Mice

Abstract

Schizophrenia has been initially associated with dysfunction in dopamine neurotransmission. 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. 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. 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. 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 neoÀ/À and DAT À/À ). 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 neoÀ/À mice. In contrast, SSR103800 failed to affect hyperactivity induced by amphetamine or naturally observed in dopamine transporter (DAT À/À ) knockout mice (10-30 mg/kg p.o.). Importantly, both classical (haloperidol) and atypical (olanzapine, clozapine and aripiprazole) antipsychotics were effective in all these models of hyperactivity. However, unlike these latter, SSR103800 did not produce catalepsy (retention on the bar test) up to 30 mg/kg p.o. 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.

TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity

“…dose-dependently suppressed hyperlocomotion in DAT −/− mice (Fig. 5C) similar to classical (haloperidol) and atypical (olanzapine and clozapine) antipsychotics (27). This finding further indicates that at least this effect of TAAR1 activation on DA-related function is independent of DAT.…”

“…Instead, we found that RO5166017 displays psychoactive properties in mice. Selective TAAR1 activation reduced anxiety in the SIH paradigm and fully prevented psychostimulant-induced and persistent hyperdopaminergia-related hyperactivity similar to the antipsychotic drug olanzapine (27). Importantly, these effects were not observed in Taar1 −/− mice, showing that the anxiolytic-and antipsychotic-like properties of RO5166017 result from selective activation of TAAR1.…”

Validation and pharmacological characterisation of MK-801-induced locomotor hyperactivity in BALB/C mice as an assay for detection of novel antipsychotics

“…For example, in male CD-1 mice, clozapine failed to reverse MK-801-induced PPI deficit at lower doses (0.1 and 0.3 mg/kg; Curzon and Decker 1998), while at higher dose (3.0 mg/kg) it reserved PPI deficit exhibited by dopamine transporter knockout mice (Powell et al 2008). Also, in female TO mice, haloperidol inhibited MK-801-induced hyperactivity only at a dose (0.1 mg/kg) that also attenuated spontaneous activity , whereas in male Swiss mice a higher dose (0.3 mg/ kg) reduced MK-801-induced hyperactivity without affecting spontaneous activity (Boulay et al 2010). …”

Relationship Between Glycine Transporter 1 Inhibition as Measured with Positron Emission Tomography and Changes in Cognitive Performances in Nonhuman Primates

“…GlyT-1 inhibitors are effective in most rodent models of schizophrenia associated with alterations in NMDA transmission (Alberati et al, 2011;Boulay et al, 2010;Yang et al, 2010). GlyT-1 inhibitors have also been reported to alleviate some of the ketamine-induced behavioural and cognitive disturbances in nonhuman primates (Roberts et al, 2010b) and in humans (D'Souza et al, 2011).…”