D-Serine diffusion through the blood-brain barrier: Effect on D-serine compartmentalization and storage

D-Serine is a co-agonist of N-methyl-D-aspartate (NMDA) receptors. It has been implicated in the etiology of schizophrenia and has shown efficacy as an adjuvant to reduce positive and negative symptoms of schizophrenia. In addition, D-serine can modulate cognition in animals when administered alone. However, the neurochemical effects of exogenous D-serine on extra- and intra-cellular D-serine brain levels are poorly understood. In this study, we used both high performance liquid chromatography (HPLC) and enzyme-based microelectrode biosensors to quantify D-serine in the rat brain. We demonstrated levels of 2.3-2.8 mu M in the extracellular medium, 4 mu M in plasma and 188 pmol/mg in brain tissue samples. An intraperitoneal (i.p.) D-serine injection (1 g/kg) produced a slow increase in extracellular D-serine concentration in the cortex despite a surge in D-serine up to 13 mM in the plasma, indicating poor diffusion through the blood-brain barrier. Using the respective volume fractions of blood, extracellular and intracellular spaces published in the literature, we estimated that D-serine intracellular stores represented more than 99% of total D-serine. These intracellular stores almost doubled 3 h after D-serine administration. Overall, our data indicate that D-serine administration increases brain extra- and intra-cellular concentrations despite weak diffusion through the blood-brain barrier. These results pave the way for a better understanding of the neurochemical mechanisms by which D-serine administration modulates cognition. (C) 2012 Elsevier Ltd. All rights reserved.