title: d-Serine diffusion through the blood-brain barrier: effect on d-serine compartmentalization and storage.
abstract: 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 2.3-2.8μM in the extracellular medium, 4μM in plasma and 188pmol/mg in brain tissue samples. An intraperitoneal (i.p.) d-serine injection (1g/kg) produced a slow increase in extracellular d-serine concentration in the cortex despite a surge in d-serine up to 13mM 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 3h 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.
authors.affiliation: Lyon Neuroscience Research Center, Plate-forme technologique AniRA-Neurochem, Team WAKE, Lyon F-69000, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Pernot
authors.forename: Caroline
authors.initials: C
authors.lastname: Maucler
authors.forename: Yannick
authors.initials: Y
authors.lastname: Tholance
authors.forename: Natalia
authors.initials: N
authors.lastname: Vasylieva
authors.forename: Gabriel
authors.initials: G
authors.lastname: Debilly
authors.forename: Loredano
authors.initials: L
authors.lastname: Pollegioni
authors.forename: Raymond
authors.initials: R
authors.lastname: Cespuglio
authors.forename: Stéphane
authors.initials: S
authors.lastname: Marinesco
mesh_terms: D000818:Animals; D015374:Biosensing Techniques; D001812:Blood-Brain Barrier; D002851:Chromatography, High Pressure Liquid; D008297:Male; D008839:Microelectrodes; D051381:Rats; D017208:Rats, Wistar; D012694:Serine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D012694:Serine