Pharmacological assessment of the role of the glycine transporter GlyT-1 in mediating high-affinity glycine uptake by rat cerebral cortex and cerebellum synaptosomes

Herdon, Hugh J.; GODFREY, Fiona; Brown, Angus M.; Coulton, Steven; Evans, J.H.; Cairns, William

doi:10.1016/s0028-3908(01)00043-0

Cited by 92 publications

(55 citation statements)

References 22 publications

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“…Specific uptake was typically 90% of total radioactivity. This is consistent with characteristics described previously for these transporters The IC 50 for the reference GlyT1 inhibitor sarcosine in human SK-N-MC cells was 60710 mM, a value that is almost identical to that previously reported for this compound in other human cells (Herdon et al, 2001).…”

Section: Resultssupporting

confidence: 91%

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

Depoortère

Dargazanli

Estenne-Bouhtou

et al. 2005

Neuropsychopharmacol

216

161

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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.

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Section: Resultssupporting

confidence: 91%

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

Depoortère

Dargazanli

Estenne-Bouhtou

et al. 2005

Neuropsychopharmacol

216

161

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“…71 NFPS blocks glycine transport in cloned GLYT1 transporters and rat brain synaptosomes with an affinity of approximately 10 nM. 44,45,72,73 NFPS potentiates NMDA transmission in rat hippocampal slices, 74 in vivo hippocampus, 75 and in rat prefrontal cortex in vivo. 76 In behavioral screens, NFPS shows antipsychotic effectiveness profile as reflected in ability to reverse PCP-induced hyperactivity 44 and enhance prepulse inhibition of the acoustic startle reflex in DBA/2 mice, 75 as well as ability to stabilize in vivo dopamine release in PCP-treated rats.…”

Section: Glycine Transport Inhibitorsmentioning

confidence: 99%

Inhibition of System A-mediated glycine transport in cortical synaptosomes by therapeutic concentrations of clozapine: implications for mechanisms of action

et al. 2004

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Clozapine is an atypical antipsychotic with particular efficacy in schizophrenia, possibly related to potentiation of brain N-methyl-D-aspartate receptor (NMDAR) -mediated neurotransmission. NMDARs are regulated in vivo by glycine, which is regulated in turn by glycine transporters. The present study investigates transport processes regulating glycine uptake into rat brain synaptosomes, along with effects of clozapine on synaptosomal glycine transport. Amino-acid uptake of amino acids was assessed in rat brain P2 synaptosomal preparations using a radiotransport assay. Synaptosomal glycine transport was inhibited by a series of amino acids and by the selective System A antagonist MeAIB (2-methylaminoisobutyric acid). Clozapine inhibited transport of both glycine and MeAIB, but not other amino acids, at concentrations associated with preferential clinical response (0.5-1 lg/ml). By contrast, other antipsychotics studied were ineffective. The novel glycine transport inhibitor Further, in meta-analytic studies, clozapine effect sizes are approximately double those of other agents. 4,5 Several theories have been proposed to account for the unique clinical effects of clozapine. These include preferential binding to serotonin (5-HT2A) receptors, 6 D4 selectivity, 7 or weak binding to D2 receptors with fast dissociation kinetics.8 However, these theories propose to account only for the decreased risk of extrapyramidal side effects associated with clozapine and other atypical antipsychotics, not for its preferential efficacy. Other newer atypicals, including risperidone and olanzapine, each share at least some of the above properties with clozapine. While these agents, like clozapine, have reduced risk of EPS, they do not appear to share clozapine's differential therapeutic efficacy, particularly against negative symptoms. Clozapine treatment typically produces trough plasma levels in the range of 0.2-1.2 mg/ml during therapeutic treatment, 9 with preferential response to clozapine being associated with plasma concentrations of approximately 0.5 mg/ml or greater in both cross-sectional 10 and longitudinal 11 studies. Two active metabolites of clozapine, desmethyl clozapine and clozapine-N-oxide, have also been described and

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“…More recently, high-affinity glycine transporter inhibitors such as N [3-(4 0 -fluorophenyl)-3-(4 0 -phenylphenoxy)propyl]sarcosine (NFPS, ALX5407) (Atkinson et al, 2001;Herdon et al, 2001) have been shown to potentiate NMDA receptor-mediated neurotransmission both in vitro (Bergeron et al, 1998) and in vivo (Chen et al, 2003); to normalize prepulse inhibition (Kinney et al, 2003;Le Pen et al, 2003); and to reverse PCP-induced DA dysregulation in vivo . However, mechanisms underlying DA reregulation produced by NMDA agonists, including both glycine and newly developed glycine transport inhibitors, remain to be determined.…”

Section: Introductionmentioning

confidence: 99%

Modulation of Striatal Dopamine Release by Glycine Transport Inhibitors

Javitt

Hashim

Sershen

2005

Neuropsychopharmacol

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Traditional models of schizophrenia have focused primarily upon dopaminergic (DA) dysregulation. In contrast, more recent models focus on dysfunction of glutamatergic systems, acting particularly through N-methyl-D-aspartate (NMDA) receptors. NMDA receptors in brain are regulated by glycine, acting via a strychnine-insensitive regulatory site, and by glycine (GlyT1) transporters that maintain low glycine levels in the immediate vicinity of the NMDA receptor complex. The present study investigates the role of NMDA receptors in the modulation of striatal dopamine release in vitro, and of glycine transport inhibitors (GTIs) as potential psychotherapeutic agents in schizophrenia. In striatum, NMDA receptors exert dual excitatory/inhibitory effects, with inhibition reflecting activity of local GABAergic feedback regulation. We have previously demonstrated effectiveness of glycine in regulating [

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Pharmacological assessment of the role of the glycine transporter GlyT-1 in mediating high-affinity glycine uptake by rat cerebral cortex and cerebellum synaptosomes

Cited by 92 publications

References 22 publications

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

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

Inhibition of System A-mediated glycine transport in cortical synaptosomes by therapeutic concentrations of clozapine: implications for mechanisms of action

Modulation of Striatal Dopamine Release by Glycine Transport Inhibitors

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