Reversal of Phencyclidine-Induced Hyperactivity by Glycine and the Glycine Uptake Inhibitor Glycyldodecylamide

Javitt, Daniel C.; Sershen, Henry; Hashim, Audrey; Lajtha, Ábel

doi:10.1016/s0893-133x(97)00047-x

Cited by 72 publications

(8 citation statements)

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“…Elevated striatal dopamine is observed in mice carrying the NR1 point mutation (Ballard et al 2002). Consistent with the present findings is the demonstration that GMS activation with either glycine or a GlyT1 inhibitor fails to attenuate AMPH-induced hyperactivity (Javitt et al 1997; Boulay et al 2010). The GlyT1 inhibitor, SSR103800, also failed to reverse hyperactivity induced by a genetic deletion of the dopamine transporter, while reversing MK801-induced hyperactivity and the hyperactivity of a NR1 hypomorphic mouse (Boulay et al 2010).…”

Section: Discussionsupporting

confidence: 92%

“…Also of note was the demonstration that both d -serine and sarcosine were more efficacious than the GMS partial agonist d -cycloserine (Tsai and Lin 2010). The clinical potentials of glycine and d -serine were initially supported by preclinical findings that demonstrated the ability of these compounds to reverse MK801/PCP-induced behaviors (Nilsson et al 1997; Javitt et al 1997). Recent studies expand on these findings indicating that glycine transporter subtype 1 (GlyT1) and DAAO blockers possess similar preclinical therapeutic profiles in their ability to reverse MK801/PCP-induced behavioral deficits (Hashimoto et al 2009; Boulay et al 2010).…”

Section: Discussionmentioning

confidence: 97%

“…Investigation of these drugs in mutant mouse strains can provide behavioral indices of the state of glutamatergic (via PCP) and dopaminergic (via AMPH) neurotransmission and potentially reveal behavioral phenotypes not observable in a drug-free state because of compensatory changes resulting from constitutive mutations (van den Buuse 2010). Pharmacological enhancement of GMS activity can reverse NMDAR blocker-induced behaviors (Javitt et al 1997; Nilsson et al 1997). Subjects with schizophrenia display enhanced AMPH-induced neurochemical changes in imaging studies, consistent with a hyperdopaminergic state (Abi-Dargham et al 2009).…”

Section: Introductionmentioning

confidence: 99%

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Discordant behavioral effects of psychotomimetic drugs in mice with altered NMDA receptor function

2010

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Rationale Enhancement of N-methyl-d-aspartate receptor (NMDAR) activity through its glycine modulatory site (GMS) is a novel therapeutic approach in schizophrenia. Brain concentrations of endogenous GMS agonist d-serine and antagonist N-acetyl-aspartylglutamate are regulated by serine racemase (SR) and glutamic acid decarboxylase 2 (GCP2), respectively. Using mice genetically, under-expressing these enzymes may clarify the role of NMDAR-mediated neurotransmission in schizophrenia. Objectives We investigated the behavioral effects of two psychotomimetic drugs, the noncompetitive NMDAR antagonist, phencyclidine (PCP; 0, 1.0, 3.0, or 6.0 mg/kg), and the indirect dopamine receptor agonist, amphetamine (AMPH; 0, 1.0, 2.0, or 4.0 mg/kg), in SR −/− and GCP2 −/+ mice. Outcome measures were locomotor activity and prepulse inhibition (PPI) of the acoustic startle reflex. Acute effects of an exogenous GMS antagonist, gavestinel (0, 3.0, or 10.0 mg/kg), on PCP-induced behaviors were examined in wild-type mice for comparison to the mutants with reduced GMS activity. Results PCP-induced hyperactivity was increased in GCP2 −/+ mice, and PCP-enhanced startle reactivity was increased in SR −/− mice. PCP disruption of PPI was unaffected in either mutant. In contrast, gavestinel attenuated PCP-induced PPI disruption without effect on baseline PPI or locomotor activity. AMPH effects were similar to controls in both mutant strains. Conclusions The results of the PCP experiments demonstrate that convergence of pharmacological and genetic manipulations at NMDARs may confound the predictive validity of these preclinical assays for the effects of GMS activation in schizophrenia. The AMPH data provide additional evidence that hyperdopaminergia in schizophrenia may be distinct from NMDAR hypofunction.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Discordant behavioral effects of psychotomimetic drugs in mice with altered NMDA receptor function

2010

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“…Rather than serving as direct glycine precursors, these compounds function similarly to selective serotonin reuptake inhibitors (SSRIs) and increase glycine levels in the brain by preventing glycine removal from the synaptic cleft, leading to endogenous increases in CSF glycine levels (138) (see Figure 1). An initial study with glycyldodeclamide, a relatively low-affinity agent, demonstrated significant reversal of PCP-induced hyperactivity in rodents (139, 140). Since then, the naturally occurring sarcosine has shown preliminary effectiveness, and high affinity GTIs have been synthesized by several pharmaceutical companies, and have shown to be effective in multiple animal models.…”

Section: Nmda-based Treatmentsmentioning

confidence: 99%

Thinking Glutamatergically: Changing Concepts of Schizophrenia Based Upon Changing Neurochemical Models

Kantrowitz¹,

Javitt²

2010

Clinical Schizophrenia & Related Psychoses

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Clinical concepts of mental illness have always been modulated by underlying theoretical considerations. For the past fifty years, schizophrenia has been considered primarily a disease of dopaminergic neurotransmission. Although this conceptualization has helped greatly in explaining the clinical effects of psychostimulants and guiding the clinical use of both typical and atypical antipsychotics, it has nevertheless shaded how we look at the disorder from both a pathophysiological and therapeutic perspective. For example, most explanatory research in schizophrenia has focused on dopamine-rich regions of the brain, with little investigation of regions of the brain that are relatively dopamine poor. Starting approximately twenty years ago, an alternative formulation of schizophrenia was proposed based upon actions of the “dissociative anesthetic” class of psychotomimetic agents, including phencyclidine (PCP), ketamine and various designer drugs. These compounds induce psychosis by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors, suggesting an alternative model for pathogenesis in schizophrenia. As opposed to dopamine, the glutamatergic system is widely distributed throughout the brain and plays a prominent role in sensory processing as well as in subsequent stages of cortical analysis. Glutamatergic theories of schizophrenia, thus, predict that cortical dysfunction will be regionally diffuse but process specific. In addition, NMDA receptors incorporate binding sites for specific endogenous brain compounds, including the amino acids glycine and D-serine and the redox modulator glutathione, and interact closely with dopaminergic, cholinergic and γ-aminobutyric acid (GABA)-ergic systems. Glutamatergic theories, thus, open new potential approaches for treatment of schizophrenia, most of which are only now entering clinical evaluation.

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“…We have previously demonstrated significant inter-correlated reversal of PCP-enhanced amphetamine-induced locomotor activity and subcortical dopamine release by glycine and high-affinity GlyT1 inhibitors (32–35). NMDAR in the brain are regulated by glutamate, which serves as the primary agonist, and glycine and D-serine, which bind to an allosteric modulatory site (36–38).…”

Section: Discussionmentioning

confidence: 99%

Modulating NMDA Receptor Function with d-Amino Acid Oxidase Inhibitors: Understanding Functional Activity in PCP-Treated Mouse Model

et al. 2016

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Deficits in N-methyl-D-aspartate receptor (NMDAR) function are increasingly linked to persistent negative symptoms and cognitive deficits in schizophrenia. Accordingly, clinical studies have been targeting the modulatory site of the NMDA receptor, based on the decreased function of NMDA receptor, to see whether increasing NMDA function can potentially help treat the negative and cognitive deficits seen in the disease. Glycine and D-serine are endogenous ligands to the NMDA modulatory site, but since high doses are needed to affect brain levels, related compounds are being developed, for example glycine transport (GlyT) inhibitors to potentially elevate brain glycine or targeting enzymes, such as D-amino acid oxidase (DAAO) to slow the breakdown and increase the brain level of D-serine. In the present study we further evaluated the effect of DAAO inhibitors 5-chloro-benzo[d]isoxazol-3-ol (CBIO) and sodium benzoate (NaB) in a phencyclidine (PCP) rodent mouse model to see if the inhibitors affect PCP-induced locomotor activity, alter brain D-serine level, and thereby potentially enhance D-serine responses. D-Serine dose-dependently reduced the PCP-induced locomotor activity at doses above 1000 mg/kg. Acute CBIO (30 mg/kg) did not affect PCP-induced locomotor activity, but appeared to reduce locomotor activity when given with D-serine (600 mg/kg); a dose that by itself did not have an effect. However, the effect was also present when the vehicle (Trappsol®) was tested with D-serine, suggesting that the reduction in locomotor activity was not related to DAAO inhibition, but possibly reflected enhanced bioavailability of D-serine across the blood brain barrier related to the vehicle. With this acute dose of CBIO, D-serine level in brain and plasma were not increased. Another weaker DAAO inhibitor sodium benzoate (NaB) (400 mg/kg), and NaB plus D-serine also significantly reduced PCP-induced locomotor activity, but without affecting plasma or brain D-serine level, arguing against a DAAO-mediated effect. However, NaB reduced plasma L-serine and based on reports that NaB also elevates various plasma metabolites, for example aminoisobutyric acid (AIB), a potential effect via the System A amino acid carrier may be involved in the regulation of synaptic glycine level to modulate NMDAR function needs to be investigated. Acute ascorbic acid (300 mg/kg) also inhibited PCP-induced locomotor activity, which was further attenuated in the presence of D-serine (600 mg/kg). Ascorbic acid may have an action at the dopamine membrane carrier and/or altering redox mechanisms that modulate NMDARs, but this needs to be further investigated. The findings support an effect of D-serine on PCP-induced hyperactivity. They also offer suggestions on an interaction of NaB via an unknown mechanism, other than DAAO inhibition, perhaps through metabolomic changes, and find unexpected synergy between D-serine and ascorbic acid that supports combined NMDA glycine- and redox-site intervention. Although mechanisms of these specific agents need to be det...

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Reversal of Phencyclidine-Induced Hyperactivity by Glycine and the Glycine Uptake Inhibitor Glycyldodecylamide

Abstract: Phencyclidine (PCP) induces

Cited by 72 publications

References 10 publications

Discordant behavioral effects of psychotomimetic drugs in mice with altered NMDA receptor function

Discordant behavioral effects of psychotomimetic drugs in mice with altered NMDA receptor function

Thinking Glutamatergically: Changing Concepts of Schizophrenia Based Upon Changing Neurochemical Models

Modulating NMDA Receptor Function with d-Amino Acid Oxidase Inhibitors: Understanding Functional Activity in PCP-Treated Mouse Model

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