The glycine transporter 1 inhibitor SSR504734 enhances working memory performance in a continuous delayed alternation task in C57BL/6 mice

Singer, Philipp; Feldon, Joram; Yee, Benjamin K.

doi:10.1007/s00213-008-1286-5

Cited by 47 publications

(34 citation statements)

References 70 publications

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“…Similarly to these findings, we found that Org-24461 selectively increased extracellular glycine concentrations in conscious rat striatum whereas increases in serine or glutamate concentrations were not seen in the microdialysis samples. Since Org-24461 and other GlyT-1 inhibitors do not exhibit major binding affinity to most neurotransmitter receptors, elevation of glycine concentrations in the vicinity of impaired NMDA receptors may be responsible for their antipsychotic [10,11,32] and procognitive [14,33] effects. It has been shown that the GlyT-1 inhibitors glycyldodecylamide and ALX5311 reduced NMDA-induced [ 3 H]dopamine release from mouse striatal slice preparations [34,35].…”

Section: Discussionmentioning

confidence: 97%

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Alterations in Brain Extracellular Dopamine and Glycine Levels Following Combined Administration of the Glycine Transporter Type-1 Inhibitor Org-24461 and Risperidone

et al. 2010

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The most dominant hypotheses for the pathogenesis of schizophrenia have focused primarily upon hyperfunctional dopaminergic and hypofunctional glutamatergic neurotransmission in the central nervous system. The therapeutic efficacy of all atypical antipsychotics is explained in part by antagonism of the dopaminergic neurotransmission, mainly by blockade of D(2) dopamine receptors. N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia can be reversed by glycine transporter type-1 (GlyT-1) inhibitors, which regulate glycine concentrations at the vicinity of NMDA receptors. Combined drug administration with D(2) dopamine receptor blockade and activation of hypofunctional NMDA receptors may be needed for a more effective treatment of positive and negative symptoms and the accompanied cognitive deficit in schizophrenia. To investigate this type of combined drug administration, rats were treated with the atypical antipsychotic risperidone together with the GlyT-1 inhibitor Org-24461. Brain microdialysis was applied in the striatum of conscious rats and determinations of extracellular dopamine, DOPAC, HVA, glycine, glutamate, and serine concentrations were carried out using HPLC/electrochemistry. Risperidone increased extracellular concentrations of dopamine but failed to influence those of glycine or glutamate measured in microdialysis samples. Org-24461 injection reduced extracellular dopamine concentrations and elevated extracellular glycine levels but the concentrations of serine and glutamate were not changed. When risperidone and Org-24461 were added in combination, a decrease in extracellular dopamine concentrations was accompanied with sustained elevation of extracellular glycine levels. Interestingly, the extracellular concentrations of glutamate were also enhanced. Our data indicate that coadministration of an antipsychotic with a GlyT-1 inhibitor may normalize hypofunctional NMDA receptor-mediated glutamatergic neurotransmission with reduced dopaminergic side effects characteristic for antipsychotic medication.

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Section: Discussionmentioning

confidence: 97%

“…This may have importance in the treatment of various types of endogenous psychosis characterized by hypofunctional NMDA receptors [9]. Similarly to antipsychotics, GlyT-1 inhibitors exert antipsychotic effects in a number of animal models of schizophrenia [10][11][12] and they also improve memory impairment in animal tests [13,14].…”

Section: Introductionmentioning

confidence: 99%

Alterations in Brain Extracellular Dopamine and Glycine Levels Following Combined Administration of the Glycine Transporter Type-1 Inhibitor Org-24461 and Risperidone

et al. 2010

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“…Slc6a9 plays a role in the regulation of glycine levels in NMDA receptor-mediated neurotransmission, and is used as a therapeutic target for schizophrenia [Bergeron et al, 1998; Mohler et al, 2011]. In vitro and in vivo modulation of Slc6a9 expression is associated with NMDA neurotransmission facilitation and working memory enhancement [Yee et al, 2006; Singer et al, 2009]. …”

Section: Discussionmentioning

confidence: 99%

The fetal brain transcriptome and neonatal behavioral phenotype in the Ts1Cje mouse model of Down syndrome

Guedj

Pennings

Ferres

et al. 2015

American J of Med Genetics Pt A

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Human fetuses with Down syndrome demonstrate abnormal brain growth and reduced neurogenesis. Despite the prenatal onset of the phenotype, most therapeutic trials have been conducted in adults. Here, we present evidence for fetal brain molecular and neonatal behavioral alterations in the Ts1Cje mouse model of Down syndrome. Embryonic day 15.5 brain hemisphere RNA from Ts1Cje embryos (n = 5) and wild type littermates (n = 5) was processed and hybridized to mouse gene 1.0 ST arrays. Bioinformatic analyses were implemented to identify differential gene and pathway regulation during Ts1Cje fetal brain development. In separate experiments, the Fox scale, ultrasonic vocalization and homing tests were used to investigate behavioral deficits in Ts1Cje pups (n = 29) versus WT littermates (n = 64) at postnatal days 3–21. Ts1Cje fetal brains displayed more differentially regulated genes (n = 71) than adult (n = 31) when compared to their age-matched euploid brains. Ts1Cje embryonic brains showed up-regulation of cell cycle markers and down-regulation of the solute-carrier amino acid transporters. Several cellular processes were dysregulated at both stages, including apoptosis, inflammation, Jak/Stat signaling, G-protein signaling, and oxidoreductase activity. In addition, early behavioral deficits in surface righting, cliff aversion, negative geotaxis, forelimb grasp, ultrasonic vocalization, and the homing tests were observed. The Ts1Cje mouse model exhibits abnormal gene expression during fetal brain development, and significant neonatal behavioral deficits in the pre-weaning period. In combination with human studies, this suggests that the Down syndrome phenotype manifests prenatally and provides a rationale for prenatal therapy to improve perinatal brain development and post-natal neurocognition.

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“…It has been proposed that compounds that elevate extracellular glycine via inhibition of GlyT-1 activity can ameliorate cognitive deficits (Liem-Moolenaar et al, 2010;Wallace et al, 2011;Nikiforuk et al, 2011;Singer et al, 2009). Therefore, the aim of our study was to determine whether a GlyT-1 inhibitor might also enhance the consequences of extinction training in subjects with cocaine self-administration histories.…”

Section: Introductionmentioning

confidence: 99%

Glycine Transporter-1 Inhibition Preceding Extinction Training Inhibits Reacquisition of Cocaine Seeking

Achat-Mendes

Dhonnchadha

Platt

et al. 2012

Neuropsychopharmacol

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Cognitive enhancers that act by increasing glycine transmission might be useful adjuncts to cocaine-cue extinction training to deter relapse. The study investigated the effects of combining treatments of the glycine transporter-1 (GlyT-1) inhibitor, Org24598, with extinction training on the subsequent reacquisition of cocaine self-administration. Squirrel monkeys and rats were trained to selfadminister cocaine under a second-order schedule of intravenous drug injection in which responding was maintained by cocaine injections and a cocaine-paired visual stimulus. During three weekly extinction sessions, saline was substituted for cocaine but responding still produced the cocaine-paired stimulus. Subjects were treated with Org24598 or vehicle, either before or after each extinction session. One week later, cocaine injections were restored, and reacquisition of cocaine self-administration was evaluated over 15 sessions. Compared with vehicle, administration of Org24598 (1.0 mg/kg in monkeys; 3.0 or 7.5 mg/kg in rats) before each extinction session significantly inhibited reacquisition of cocaine self-administration in each species. In contrast, administration of Org24598 (1.0 mg/kg in monkeys) following, rather than preceding, each extinction session did not affect reacquisition compared with vehicle. When extinction training was replaced by cocaine self-administration or abstinence control conditions, treatment with the same doses of Org24598 resulted in reacquisition that was significantly more rapid than the reacquisition observed when Org24598 was administered before extinction training sessions. The results support the potential clinical utility of GlyT-1 inhibitor pretreatments combined with cocaine-cue extinction training to inhibit relapse.

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The glycine transporter 1 inhibitor SSR504734 enhances working memory performance in a continuous delayed alternation task in C57BL/6 mice

Cited by 47 publications

References 70 publications

Alterations in Brain Extracellular Dopamine and Glycine Levels Following Combined Administration of the Glycine Transporter Type-1 Inhibitor Org-24461 and Risperidone

Alterations in Brain Extracellular Dopamine and Glycine Levels Following Combined Administration of the Glycine Transporter Type-1 Inhibitor Org-24461 and Risperidone

The fetal brain transcriptome and neonatal behavioral phenotype in the Ts1Cje mouse model of Down syndrome

Glycine Transporter-1 Inhibition Preceding Extinction Training Inhibits Reacquisition of Cocaine Seeking

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