Neurochemical, Electrophysiological and Pharmacological Profiles of the Selective Inhibitor of the Glycine Transporter-1 SSR504734, a Potential New Type of Antipsychotic

Abstract

Noncompetitive N-methyl-D-aspartate (NMDA) blockers induce schizophrenic-like symptoms in humans, presumably by impairing glutamatergic transmission. Therefore, a compound potentiating this neurotransmission, by increasing extracellular levels of glycine (a requisite co-agonist of glutamate), could possess antipsychotic activity. Blocking the glycine transporter-1 (GlyT1) should, by increasing extracellular glycine levels, potentiate glutamatergic neurotransmission. SSR504734, a selective and reversible inhibitor of human, rat, and mouse GlyT1 (IC 50 ¼ 18, 15, and 38 nM, respectively), blocked reversibly the ex vivo uptake of glycine (mouse cortical homogenates: ID 50 : 5 mg/kg i.p.), rapidly and for a long duration. In vivo, it increased (minimal efficacious dose (MED): 3 mg/kg i.p.) extracellular levels of glycine in the rat prefrontal cortex (PFC). This resulted in an enhanced glutamatergic neurotransmission, as SSR504734 potentiated NMDA-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices (minimal efficacious concentration (MEC): 0.5 mM) and intrastriatal glycine-induced rotations in mice (MED: 1 mg/kg i.p.). It normalized activity in rat models of hippocampal and PFC hypofunctioning (through activation of presynaptic CB 1 receptors): it reversed the decrease in electrically evoked [3 H]acetylcholine release in hippocampal slices (MEC: 10 nM) and the reduction of PFC neurons firing (MED: 0.3 mg/kg i.v.). SSR504734 prevented ketamine-induced metabolic activation in mice limbic areas and reversed MK-801-induced hyperactivity and increase in EEG spectral energy in mice and rats, respectively (MED: 10-30 mg/kg i.p.). In schizophrenia models, it normalized a spontaneous prepulse inhibition deficit in DBA/2 mice (MED: 15 mg/kg i.p.), and reversed hypersensitivity to locomotor effects of d-amphetamine and selective attention deficits (MED: 1-3 mg/kg i.p.) in adult rats treated neonatally with phencyclidine. Finally, it increased extracellular dopamine in rat PFC (MED: 10 mg/kg i.p.). The compound showed additional activity in depression/anxiety models, such as the chronic mild stress in mice (10 mg/kg i.p.), ultrasonic distress calls in rat pups separated from their mother (MED: 1 mg/kg s.c.), and the increased latency of paradoxical sleep in rats (MED: 30 mg/kg i.p.). In conclusion, SSR504734 is a potent and selective GlyT1 inhibitor, exhibiting activity in schizophrenia, anxiety and depression models. By targeting one of the primary causes of schizophrenia (hypoglutamatergy), it is expected to be efficacious not only against positive but also negative symptoms, cognitive deficits, and comorbid depression/anxiety states.

Glycine Transporter Type 1 Occupancy by Bitopertin: a Positron Emission Tomography Study in Healthy Volunteers

“…Indeed GlyT1 has been found to be expressed not only in glial cells but also in neurons, particularly in glutamatergic neurons of cortex and hippocampus, whereas in more caudal brain regions it is predominantly expressed in glial cells surrounding glutamatergic synapses (Smith et al, 1992;Cubelos et al, 2005). In addition, the increased levels of extracellular glycine in rat striatum induced by bitopertin, as measured by microdialysis (Alberati et al, 2012), were similar to those reported for SSR504734, another GRI, where the microdialysis probe was implanted in medial prefrontal cortex (Depoortère et al, 2005). Figure 3 Relationship between bitopertin pre-and post-scan mean plasma concentration and GlyT1 occupancy in healthy volunteers on last day of treatment in the (a) cerebellum, (b) pons, and (c) thalamus, derived by two-tissue five-parameter (2T5P) model, simplified reference tissue model (SRTM), and pseudoreference tissue model (PRTM) as well as (d) on last day of treatment and 2 days after drug discontinuation in the thalamus.…”

Neonatal Phencyclidine Treatment in Mice Induces Behavioral, Histological and Neurochemical Abnormalities in Adulthood

“…3) It has been reported that rats injected subcutaneously (s.c.) with phencyclidine (PCP), a noncompetitive NMDA receptor antagonist, at 10 mg/kg once a day during the postnatal development stage (postnatal days 7, 9 and 11) exhibit an increase in spontaneous motor activity, impairment of prepulse inhibition and behavioral changes in respect of learning and cognition after attaining maturation. [4][5][6][7] When rats neonatally administered PCP were examined for any changes in the binding capacity of NMDA receptors and g-aminobutyrate A (GABA A ) receptors at maturity by autoradiography using 8) These results suggest that the density of NMDA and GABA A receptors may increase during maturation in animals if they had been administered PCP at a postnatal development stage corresponding to the sensitive phase for the acquisition of higher neural function. 8) In the present study, we investigated brain function from the behavioral, anatomical and neurochemical viewpoints in mice injected with PCP at 10 mg/kg on postnatal days 7, 9 and 11.…”

Selective Mitochondrial Targeting Exerts Anxiolytic Effects In Vivo

“…Sarcosine (N-methylglycine) has been discussed in the context of psychiatric disorders as an inhibitor of the glycine transporter. Inhibition of glycine transporters has been suggested to both induce and attenuate anxietyrelated behavior (Depoortere et al, 2005;Labrie et al, 2009). AMP is involved in purine metabolism, components of which have been associated with symptoms of major psychiatric disorders (Yao et al, 2012) whereas ascorbic acid is a known antioxidant.…”