Long-Term Treatment With Morphine Increases the D-Serine Content in the Rat Brain by Regulating the mRNA and Protein Expressions of Serine Racemase and D-Amino Acid Oxidase

Yoshikawa, Masanobu; Shinomiya, Takashi; Takayasu, Naoko; Tsukamoto, Hideo; Kawaguchi, Mitsuru; Kobayashi, Hiroyuki; Oka, Tetsuo; Hashimoto, Atsushi

doi:10.1254/jphs.08030fp

Cited by 19 publications

(13 citation statements)

References 34 publications

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“…It was unclear from the data in the previous study whether this effect was due to increased/decreased SR protein synthesis, which has been associated with LPS treatment [29] or an alteration in the m-SR: d-SR equilibrium. Alterations in SR expression have also been reported after acute and chronic administrations of morphine [30,31] and ketamine [22,25]. Based upon these observations we determined the effect of incubation with GBP and PGB on m-SR and d-SR in PC-12 cells.…”

Section: Discussionmentioning

confidence: 69%

Gabapentin and (S)-pregabalin decrease intracellular d-serine concentrations in PC-12 cells

Singh

Paul

Torjman

et al. 2013

Neuroscience Letters

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The effects of gabapentin (GBP) and (S)-pregabalin (PGB) on the intracellular concentrations of D-serine and the expression of serine racemase (SR) in PC-12 cells were determined. Intracellular D-serine concentrations were determined using an enantioselective capillary electrophoresis assay with laser-induced fluorescence detection. Increasing concentrations of GBP, 0.1 – 20 μM, produced a significant decrease in D-serine concentration relative to control, 22.9 ± 6.7% at 20 μM (*p < 0.05), with an IC50 value of 3.40 ± 0.29 μM. Increasing concentrations of PGB, 0.1 – 10 μM, produced a significant decrease in D-serine concentration relative to control, 25.3 ± 7.6% at 10 μM (*p < 0.05), with an IC50 value of 3.38 ± 0.21 μM. The compounds had no effect on the expression of monomeric-SR or dimeric-SR as determined by Western blotting. The results suggest that incubation of PC-12 cells with GBP and PGB reduced the basal activity of SR, which is most likely a result of the decreased Ca+2 flux produced via interaction of the drugs with the α2-δ subunit of voltage-gated calcium channels. D-serine is a co-agonist of the N-methyl D-aspartate receptor (NMDAR) and reduced D-serine concentrations have been associated with reduced NMDAR activity. Thus, GBP and PGB may act as indirect antagonists of NMDAR, a mechanism that may contribute to the clinical effects of the drugs in neuropathic pain.

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Section: Discussionmentioning

confidence: 69%

Gabapentin and (S)-pregabalin decrease intracellular d-serine concentrations in PC-12 cells

Singh

Paul

Torjman

et al. 2013

Neuroscience Letters

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“…Morphine administration increases steadystate levels of Srr mRNA and protein in rat brain (57), but the regulatory mechanism governing Srr expression remains largely unexplored. The present biochemical and histological experiments demonstrate that marked reductions of serine enantiomers do not affect the expression levels of Srr (Fig.…”

Section: Discussionmentioning

confidence: 99%

Brain-specific Phgdh Deletion Reveals a Pivotal Role for l-Serine Biosynthesis in Controlling the Level of d-Serine, an N-methyl-d-aspartate Receptor Co-agonist, in Adult Brain

Yang

Wada

Yoshida

et al. 2010

Journal of Biological Chemistry

117

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In mammalian brain, D-serine is synthesized from L-serine by serine racemase, and it functions as an obligatory coagonist at the glycine modulatory site of N-methyl-D-aspartate (NMDA)-selective glutamate receptors. Although diminution in D-serine level has been implicated in NMDA receptor hypofunction, which is thought to occur in schizophrenia, the source of the precursor L-serine and its role in D-serine metabolism in adult brain have yet to be determined. We investigated whether L-serine synthesized in brain via the phosphorylated pathway is essential for Dserine synthesis by generating mice with a conditional deletion of D-3-phosphoglycerate dehydrogenase (Phgdh; EC 1.1.1.95). This enzyme catalyzes the first step in L-serine synthesis via the phosphorylated pathway. HPLC analysis of serine enantiomers demonstrated that both L-and D-serine levels were markedly decreased in the cerebral cortex and hippocampus of conditional knock-out mice, whereas the serine deficiency did not alter protein expression levels of serine racemase and NMDA receptor subunits in these regions. The present study provides definitive proof that Lserine-synthesized endogenously via the phosphorylated pathway is a key rate-limiting factor for maintaining steadystate levels of D-serine in adult brain. Furthermore, NMDAevoked transcription of Arc, an immediate early gene, was diminished in the hippocampus of conditional knock-out mice. Thus, this study demonstrates that in mature neuronal circuits L-serine availability determines the rate of Dserine synthesis in the forebrain and controls NMDA receptor function at least in the hippocampus.Glutamate is the principal excitatory neurotransmitter in mammalian brain, acting on ionotropic and metabotropic glutamate receptors. Ionotropic glutamate receptors can be divided into three classes based on their preference for the ligands N-methyl-D-aspartate (NMDA), 3 ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, and kainate. Among these receptors, NMDA receptors have been implicated in synapse refinement, synaptic plasticity, and learning/memory as well as brain pathologies including excitotoxicity and psychiatric diseases (for review, see Refs. 1-3). Two NMDA receptor subunits, NR1 and NR2, form tetramers that comprise the functional receptors. For the NMDA receptor to function as a ligand-gated ion channel, a co-agonist must occupy the glycine modulatory site on NR1 coincident with glutamate binding to the transmitter recognition site on NR2 (4 -6).D-Serine occurs naturally in the adult brain of higher vertebrates and is particularly enriched in forebrain regions (7). This D-amino acid acts as an endogenous co-agonist at the glycine modulatory site of NMDA receptors (for review, see Refs. 8 -11). In the telencephalon, where D-serine is abundant (12), its distribution pattern resembles that of NR2A/B subunits (13). In contrast, immunoreactivity for free glycine is very low in telencephalon and is detected primarily in the hindbrain and hypothalamus, where NR2A/B expression is weaker than in ...

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“…This phenomenon seems to enhance glutamate signals in the synaptic cleft, which in turn give more opportunity for the stimulation of NMDA receptors ( Figure 4). In this sense, D-serine, a key molecule that activates NMDA receptors as an allosteric agonist (66), seems to also be involved in this anti-opioid system because chronic morphine induced up-regulation of glial racemase to increase D-serine levels (67). The knock-down of spinal cord postsynaptic density protein-95 (PSD-95), a scaffold protein for NMDA receptors, prevented the development of morphine tolerance in rats (68) .…”

Section: Other Systems That Support the Anti-opioid Nmda Receptor Systemmentioning

confidence: 99%

Mechanisms underlying morphine analgesic tolerance and dependence

Ueda¹

2009

Front Biosci

101

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The mechanisms underlying opioid tolerance are not fully understood, but appear to be comprised of two types of plasticity or counter-adaptation, at the cellular level and through neuronal circuits. Current studies mostly emphasize the cellular adaptation mechanisms, which include altered gene expression and receptor desensitization due to phosphorylation and endocytosis. However, the mechanisms underlying opioid tolerance and dependence are not always explained by cellular adaptation mechanisms alone. This review focuses on the plasticity in neuronal circuits achieved through an enhancement of synaptic activities between glutamate and NMDA receptor due to up-regulation of receptor and racemase to produce D-serine, an allosteric NMDA receptor agonist, and down-regulation of glutamate transporter, all which contribute to the counterbalance of opioid actions or anti-opioid mechanisms underlying opioid tolerance. This anti-opioid system is supposed to be also augmented by altered expression of key molecules regulating through neuron-glial networks. This review also introduces a new approach using in vivo electroporation to identify the brain loci responsible for morphine tolerance and dependence.

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Long-Term Treatment With Morphine Increases the D-Serine Content in the Rat Brain by Regulating the mRNA and Protein Expressions of Serine Racemase and D-Amino Acid Oxidase

Cited by 19 publications

References 34 publications

Gabapentin and (S)-pregabalin decrease intracellular d-serine concentrations in PC-12 cells

Gabapentin and (S)-pregabalin decrease intracellular d-serine concentrations in PC-12 cells

Brain-specific Phgdh Deletion Reveals a Pivotal Role for l-Serine Biosynthesis in Controlling the Level of d-Serine, an N-methyl-d-aspartate Receptor Co-agonist, in Adult Brain

Mechanisms underlying morphine analgesic tolerance and dependence

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