Correspondence| Volume 73, ISSUE 12, e33-e34, June 15, 2013

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Is D-Cycloserine a Prodrug for D-Serine in the Brain?

      D-cycloserine (DCS), (4R)-4-amino-1,2-oxazolidin-3-one, is a partial agonist at the strychnine-insensitive glycine modulatory site associated with the N-methyl-D-aspartate (NMDA) receptor complex. DCS is also a less efficient ligand of NMDA receptor function than endogenous full agonists, such as glycine and D-serine. At high doses, DCS acts as an antagonist by displacing more efficacious endogenous agonists, but at moderate doses, DCS facilitates glutamatergic neurotransmission via the NMDA receptor. Recent meta-analysis shows that glycine, D-serine, and sarcosine (N-methylglycine), an endogenous glycine transporter-1 inhibitor, are more effective than DCS in improving the overall psychopathology in patients with schizophrenia receiving antipsychotic drugs (
      • Tsai G.E.
      • Lin P.Y.
      Strategies to enhance N-methyl-D-aspartate receptor-mediated neurotransmission in schizophrenia. A critical review and meta-analysis.
      ). This suggests a relatively narrow therapeutic window for DCS, most likely due to its partial agonist properties.
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