Reversal of Phencyclidine-Induced Dopaminergic Dysregulation by N-Methyl-D-Aspartate Receptor/Glycine-site Agonists

Javitt, Daniel C.; Balla, Andrea; Burch, Sarah; Suckow, R F; Xie, Shan; Sershen, Henry

doi:10.1038/sj.npp.1300313

Cited by 98 publications

(86 citation statements)

References 62 publications

(67 reference statements)

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“…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. 77 Those studies strongly support the initial conjecture regarding the importance of glycine transport to NMDA regulation. The present findings suggest that GLYT1 transporters may not play an exclusive role in glycine modulation, but that other brain transport processes may also be important and may contribute to therapeutic effectiveness of clozapine.…”

Section: Glycine Transport Inhibitorssupporting

confidence: 61%

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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Section: Glycine Transport Inhibitorssupporting

confidence: 61%

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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“…SSR504734 was found to have beneficial effects in adult rats neonatally treated with PCP on two behavioral aspects relevant to the pathology: (1) hypersensitivity to an acute challenge with d-amphetamine (that has been reported in schizophrenic patients during acute psychotic episodes; Laruelle, 2000) and (2) selective attention deficit (a cognitive process that is greatly affected in schizophrenia, and considered to be a predominant characteristic of the disease; Brébion et al, 2000). The beneficial effects of SSR504734 on the former are consonant with the recent findings that chronic treatment with NFPS or glycine prevented the potentiation of d-amphetamine-induced DA release in the striatum seen with chronic administration of PCP (Javitt et al, 2004). To the extent that this hypersensitivity to d-amphetamine reflects an abnormal sensitivity of subcortical DA systems, conducive to the genesis of florid symptoms in schizophrenic patients (Laruelle, 2000), the blunting effect of SSR504734 provides an additional experimental argument for a potential activity of the compound against positive symptomatology.…”

Section: Ssr504734 Shows Activity In Various Tests Predictive Of Antimentioning

confidence: 69%

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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“…[106][107][108] More recent studies have been performed with selective, high-affinity GTIs such as N[3-(4 0 -fluorophenyl)-3-(4 0 -phenylphenoxy)propyl]-sarcosine (NFPS) 109 or Org 24598. 110 As with GDA, high affinity GTIs have been found to reverse PCP-induced hyperactivity 111 and dopaminergic hyperreactivity 112 in rodents, and to potentiate hippocampal LTP 113 and NMDAR-dependent responses in prefrontal cortical neurons. 114 GTIs also reverse PPI abnormalities in DBA/2J mice 113 and rats with neonatal hippocampal lesions, 115 supporting a potential role of GTIs in treatment of schizophrenia.…”

Section: Glutamatergicmentioning

confidence: 99%

Glutamate as a therapeutic target in psychiatric disorders

2004

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Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Glutamatergic neurotransmission may be modulated at multiple levels, only a minority of which are currently being exploited for pharmaceutical development. Ionotropic receptors for glutamate are divided into N-methyl-D-aspartate receptor (NMDAR) and AMPA receptor subtypes. NMDAR have been implicated in the pathophysiology of schizophrenia. The glycine modulatory site of the NMDAR is currently a favored therapeutic target, with several modulatory agents currently undergoing clinical development. Of these, the full agonists glycine and D-serine have both shown to induce significant, large effect size reductions in persistent negative and cognitive symptoms when added to traditional or newer atypical antipsychotics in double-blind, placebo-controlled clinical studies. Glycine (GLYT1) and small neutral amino-acid (SNAT) transporters, which regulate glycine levels, represent additional targets for drug development, and may represent a site of action of clozapine. Brain transporters for D-serine have recently been described. Metabotropic glutamate receptors are positively (Group I) or negatively (Groups II and III) coupled to glutamatergic neurotransmission. Metabotropic modulators are currently under preclinical development for neuropsychiatric conditions, including schizophrenia, depression and anxiety disorders. Other conditions for which glutamate modulators may prove effective include stroke, epilepsy, Alzheimer disease and PTSD. Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Approximately 60% of neurons in the brain, including all cortical pyramidal neurons and thalamic relay neurons, utilize glutamate as their primary neurotransmitter. 1 As a result, virtually all thalamocortical, corticocortical and corticofugal neurotransmission in the brain is mediated by glutamate. Glutamate is released from presynaptic terminals in response to neuronal depolarization, and is recycled by excitatory amino acid (EAA) transporters located on both neurons and glia. 2 Within glia, glutamate is converted to glutamine and released into extracellular fluid from which it is reabsorbed into presynaptic terminals and converted back to glutamate via action of neuronal glutaminase. Up to 2/3 of brain energy metabolism is related to reuptake and recycling of glutamate. 3 As such, functional imaging modalities, such as PET and fMRI, indexing activity primarily of brain glutamatergic systems. 4 The exchange of glutamine from glia to neurons is accomplished by coordinated actions of two transport systems, systems N and A, both of which are members of sodium-dependent neutral amino acid (SNAT) family of transporters. 5 These transport systems also transport precursors for cysteine and glycine, which are precursors to glutathione synthesis. 6 As these transporters are electrogenic, glutamate transporters may also participate in cellular signaling. 7 As with glutamate and GABA transporters, these recycling systems may constitute interesti...

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Reversal of Phencyclidine-Induced Dopaminergic Dysregulation by N-Methyl-D-Aspartate Receptor/Glycine-site Agonists

Cited by 98 publications

References 62 publications

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

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

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

Glutamate as a therapeutic target in psychiatric disorders

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