Neurochemical and behavioral profiling of the selective GlyT1 inhibitors ALX5407 and LY2365109 indicate a preferential action in caudal vs. cortical brain areas

Perry, Kenneth W.; Falcone, Julie F.; Fell, Matthew; Ryder, John; Yu, Hong; Love, Patrick L.; Katner, Jason; Gordon, Kimberly D.; Wade, Mark; Man, Teresa; Nomikos, George G.; Phebus, Lee A.; Cauvin, Annick; Johnson, Kirk W.; Jones, Carrie K.; Hoffmann, Beth J.; Sandusky, George E.; Walter, Magnus W.; Porter, Warren J.; Yang, Lijuan; Merchant, Kalpana; Shannon, Harlan E.; Svensson, Kjell

doi:10.1016/j.neuropharm.2008.06.016

Cited by 77 publications

(51 citation statements)

References 32 publications

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“…These transporters may have particular importance in regulation of synaptic glycine concentrations when GlyT-1 is blocked by specific inhibitors. Selective GlyT-1 inhibitors like NFPS exhibit only low affinity interaction with System A-mediated glycine transport and they are almost completely ineffective in inhibition of GlyT-2 activity [45,47]. The dual involvement of GlyT-1 and GlyT-2 in glycine-induced glutamate efflux was demonstrated by using confocal microscopy experiments in the spinal cord and by direct release measurements in rat cerebral cortex synaptosomes [46,48].…”

Section: Discussionmentioning

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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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: 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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“…It has been shown that sarcosine-derived inhibitors exhibit an allosteric and irreversible inhibition, whereas nonsarcosine-derived structures were found to be reversible competitive inhibitors (Mezler et al, 2008). Consistent with an irreversible inhibition, sarcosine-derived inhibitors produce slowly increasing and sustained locomotor impairments (Perry et al, 2008), pointing to cumulating binding associated with a poorly controllable degree of inhibition. Nonsarcosine-derived structures may exhibit a more appropriate safety margin, not only because of their reversible mode of action, but also because of the competitive and surmountable transport inhibition.…”

Section: Glycine Transporter 1 Inhibitorsmentioning

confidence: 99%

Glutamatergic (N-Methyl-d-aspartate Receptor) Hypofrontality in Schizophrenia: Too Little Juice or a Miswired Brain?

Marek

Behl²,

Bespalov³

et al. 2009

Mol Pharmacol

139

115

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Dopamine D2 receptor blockade has been an obligate mechanism of action present in all medications that effectively treat positive symptoms of schizophrenia (e.g., delusions and hallucinations) and have been approved by regulatory agencies since the 1950s. Blockade of 5-hydroxytrypatmine 2A receptors plays a contributory role in the actions of the second generation of antipsychotic drugs, the so-called atypical antipsychotics. Nevertheless, substantial unmet medical needs remain for the treatment of negative symptoms and cognitive dysfunction. Recognition that dissociative anesthetics block the N-methyl-D-aspartate (NMDA) receptor channel has inspired a search for glutamatergic therapeutic mechanisms because ketamine and phencyclidine are known to induce psychotic-like symptoms in healthy volunteers and exacerbate the symptoms of patients with schizophrenia. Current pathophysiological theories of schizophrenia emphasize that hypofunction of NMDA receptors at critical sites in local circuits modulate the function of a given brain region or control projections from one region to another (e.g., hippocampal-cortical or thalamocortical projections). The demonstration that a metabotropic glutamate 2/3 (mGlu2/3) receptor agonist prodrug decreased both positive and negative symptoms of schizophrenia raised hopes that glutamatergic mechanisms may provide therapeutic advantages. In addition to discussing the activation of mGlu2 receptors with mGlu2/3 receptor agonists or mGlu2 receptor positive allosteric modulators (PAMs), we discuss other methods that may potentially modulate circuits with hypofunctional NMDA receptors such as glycine transporter inhibitors and mGlu5 receptor PAMs. The hope is that by modulating glutamatergic neurotransmission, the dysfunctional circuitry of the schizophrenic brain (both local circuits and long-loop pathways) will be improved. Dopamine and serotonin, as opposed to emerging interest in glutamate, played a dominant role during the formative years of modern psychopharmacology when thinking about the pathophysiology and treatment of schizophrenia. Models derived from studying the behavioral effects of amphetamine and serotonergic hallucinogens were emphasized (Table 1). The seminal observations by Arvid Carlsson and his colleagues in the late early 1960s that first postulated functional dopamine receptor blockade as a necessary therapeutic action by the phenothiazine and butyrophenone structural classes set the stage for our current mechanistic understanding of all antipsychotic drugs currently used today (Carlsson and Lindqvist, 1963). The emergence of in vitro receptor binding and positron emission topography receptor occupancy studies in healthy volunteers and patients identified dopamine D2 receptor Article, publication date, and citation information can be found at

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“…The sarcosine-like GlyT1 inhibitor ORG24461 has been described to block amphetamineinduced motor hyperactivity in male NMRI mice (Harsing et al, 2003). Pronounced motor dysfunction, respiratory failure and seizure effects described in mice with such compounds (Perry et al, 2008) suggest that their action on amphetamine may be due to non-specific reversal effects. The reversible and non sarcosine-like GlyT1 inhibitors SSR103800 and SSR504734 did not produce such adverse effects in rodents (Depoortere et al, 2005;Boulay et al, 2008;Singer et al, 2009).…”

Section: Effect Of the Glyt1 Inhibitor Ssr103800 On Hyperactivity Resmentioning

confidence: 99%

The Glycine Transporter-1 Inhibitor SSR103800 Displays a Selective and Specific Antipsychotic-like Profile in Normal and Transgenic Mice

Boulay

Bergis

Avenet

et al. 2009

Neuropsychopharmacol

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Schizophrenia has been initially associated with dysfunction in dopamine neurotransmission. However, the observation that antagonists of the glutamate N-methyl-D-aspartate (NMDA) receptor produce schizophrenic-like symptoms in humans has led to the idea of a dysfunctioning of the glutamatergic system via its NMDA receptor. As a result, there is a growing interest in the development of pharmacological agents with potential antipsychotic properties that enhance the activity of the glutamatergic system via a modulation of the NMDA receptor. Among them are glycine transporter-1 (GlyT1) inhibitors such as SSR103800, which indirectly enhance NMDA receptor function by increasing the glycine (a co-agonist for the NMDA receptor) levels in the synapse. This study aimed at investigating the potential antipsychotic-like properties of SSR103800, with a particular focus on models of hyperactivity, involving either drug challenge (ie, amphetamine and MK-801) or transgenic mice (ie, NMDA Nr1 neoÀ/À and DAT À/À ). Results showed that SSR103800(10-30 mg/kg p.o.) blocked hyperactivity induced by the non-competitive NMDA receptor antagonist, MK-801 and partially reversed spontaneous hyperactivity of NMDA Nr1 neoÀ/À mice. In contrast, SSR103800 failed to affect hyperactivity induced by amphetamine or naturally observed in dopamine transporter (DAT À/À ) knockout mice (10-30 mg/kg p.o.). Importantly, both classical (haloperidol) and atypical (olanzapine, clozapine and aripiprazole) antipsychotics were effective in all these models of hyperactivity. However, unlike these latter, SSR103800 did not produce catalepsy (retention on the bar test) up to 30 mg/kg p.o. Together these findings show that the GlyT1 inhibitor, SSR103800, produces antipsychotic-like effects, which differ from those observed with compounds primarily targeting the dopaminergic system, and has a reduced side-effect potential as compared with these latter drugs.

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Neurochemical and behavioral profiling of the selective GlyT1 inhibitors ALX5407 and LY2365109 indicate a preferential action in caudal vs. cortical brain areas

Cited by 77 publications

References 32 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

Glutamatergic (N-Methyl-d-aspartate Receptor) Hypofrontality in Schizophrenia: Too Little Juice or a Miswired Brain?

The Glycine Transporter-1 Inhibitor SSR103800 Displays a Selective and Specific Antipsychotic-like Profile in Normal and Transgenic Mice

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