Spatial Memory Deficits Induced by Perinatal Treatment of Rats with PCP and Reversal Effect of D-Serine

Andersen, Janne Damm; Pouzet, Bruno

doi:10.1038/sj.npp.1300394

Cited by 119 publications

(71 citation statements)

References 54 publications

(61 reference statements)

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“…This normalization of impairment of selective attention in rats and of spontaneous deficit of PPI (a putative marker of information processing) in DBA/2 mice is promising in terms of a beneficial activity of SSR504734 on those cognitive processes that are impaired in schizophrenic patients. Furthermore, the recent demonstration that the direct glycine agonist d-serine reversed the deleterious effects produced by a similar neonatal PCP treatment in a spatial memory task in rats (Andersen and Pouzet, 2004) buttresses the notion that a proglycinergic strategy might have a positive impact on multiple facets of cognitive deficiency in schizophrenia. This particular aspect deserves further investigation.…”

Section: Ssr504734 Shows Activity In Various Tests Predictive Of Antimentioning

confidence: 89%

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: Ssr504734 Shows Activity In Various Tests Predictive Of Antimentioning

confidence: 89%

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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“…18 In animal models, gultamatergic antagonists, such as PCP, disrupt PPI, spatial learning and social interaction. 135,137,[139][140][141] Increased locomotion and stereotyped behaviour were also evident in rats treated with single and repeated doses of PCP. 107,142,143 The social interaction deficits and stereotypy caused by PCP administration were reversed by conventional and novel antipsychotic medications.…”

Section: Pharmacologic Animal Modelsmentioning

confidence: 96%

Contribution of nonprimate animal models in understanding the etiology of schizophrenia

Lazar

Neufeld²,

Cain³

2011

jpn

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“…Treatments that can augment the synaptic concentrations of D-serine or glycine are, therefore, possible therapies (Javitt, 2004). Indeed, rodents treated with NMDA receptor antagonist show behavioral endotypes of schizophrenia that can be partially ameliorated by D-serine (Andersen and Pouzet, 2004;Lipina et al, 2005). The role of D-serine as a cognitive enhancer in the normal brain is not as well documented.…”

Section: D-serine In Psychiatric Diseasementioning

confidence: 99%

D-Serine Augments NMDA-NR2B Receptor-Dependent Hippocampal Long-Term Depression and Spatial Reversal Learning

Duffy

Labrie

Roder

2007

Neuropsychopharmacol

157

135

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The contributions of hippocampal long-term depression (LTD) to explicit learning and memory are poorly understood. Electrophysiological and behavioral studies examined the effects of modulating NMDA receptor-dependent LTD on spatial learning in the Morris water maze (MWM). The NMDA receptor co-agonist D-serine substantially enhanced NR2B-dependent LTD, but not long-term potentiation (LTP) or depotentiation, in hippocampal slices from adult wild type mice. Exogenous D-serine did not alter MWM acquisition, but substantially enhanced subsequent reversal learning of a novel target location and performance in a delayed-matchingto-place task. Conversely, an NR2B antagonist disrupted reversal learning and promoted perseveration. Endogenous synaptic D-serine likely saturates during LTP induction because exogenous D-serine rescued deficient LTP and MWM acquisition in Grin1 D481N mutant mice having a lower D-serine affinity. Thus, D-serine may enhance a form of hippocampal NR2B-dependent LTD that contributes to spatial reversal learning. By enhancing this form of synaptic plasticity, D-serine could improve cognitive flexibility in psychiatric disorders characterized by perseveration of aberrant ideation or behaviors.

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Spatial Memory Deficits Induced by Perinatal Treatment of Rats with PCP and Reversal Effect of D-Serine

Cited by 119 publications

References 54 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

Contribution of nonprimate animal models in understanding the etiology of schizophrenia

D-Serine Augments NMDA-NR2B Receptor-Dependent Hippocampal Long-Term Depression and Spatial Reversal Learning

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