Alterations in Plasma Levels of Amino Acids after Intracerebroventricular Administration of L-Serine or D-Serine in Conscious and Freely Moving Rats

L-Serine has a role in cellular proliferation, being a precursor for protein synthesis, and is also important for brain development. D-Serine plays a role as the endogenous co-agonist at the glycine site on the N-methyl-D-aspartate (NMDA) receptors in the brain. Accumulating evidence suggests that abnormality of D-serine levels might be involved in the pathophysiology of schizophrenia. Using the automated blood sampling system, we examined whether or not intracerebroventricular (icv) infusion of Land D-isomers of serine could affect plasma levels of amino acids in conscious and freely moving rats. The icv infusion of L-serine significantly decreased the plasma levels of glycine, glutamate, and Dserine, but not glutamine and L-serine. Furthermore, the icv infusion of D-serine significantly decreased the plasma levels of glycine, glutamate, and L-serine, but not glutamine. Expectedly, a marked increase of plasma D-serine was detected after icv infusion of D-serine. These findings suggest that the metabolic pathway for Land D-serine may be markedly different in the rat brain. INTRODUCTION Several lines of evidence suggest that a dysfunction in the glutamatergic neurotransmission via N-methyl-Daspartate (NMDA) receptors might be involved in the pathophysiology of neuropsychiatric diseases, including schizophrenia, mood disorders, Alzheimer’s disease, and autism [19]. Amino acids, including glutamate, glutamine, glycine, Lserine, and D-serine, have been shown to be associated with the glutamatergic neurotransmission via NMDA receptors [10]. Previously, we reported alterations in the blood levels of these amino acids in patients with schizophrenia, Alzheimer’s disease and autism [11-14]. Thus, we considered that it would be of great interest to examine the potential use of the blood levels of these amino acids as biological markers for neuropsychiatric diseases.. L-Serine has been shown to play a role in cellular proliferation, as it is a precursor for nucleotide synthesis [15-17]. In addition, after the first reports of serine deficiency disorders (3-phosphoglycerate dehydrogenase (3-PGDH) deficiency and 3-phosphoserine phosphatase (3-PSP) deficiency)), it also became clear that L-serine and L-serinederived metabolites are important for brain development and function [17-25]. In contrast, D-serine, an isomer of Lserine, plays a role as a key co-agonist for NMDA receptors [26-32]. D-Serine is produced by serine racemase (SRR) from L-serine, and D-serine has been shown to be metabolized by D-amino acid oxidase (DAAO) in the brain. Several *Address correspondence to this author at the Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba 260-8670, Japan; Tel: +81-43-226-2147; Fax: +81-43-226-2150; E-mail: [email protected] reports have demonstrated that abnormality of D-serine levels might be implicated in the pathophysiology of schizophrenia [6-8,11,12,33-36]. Thus, it may be of great interest to study the metabolic pathways of Land D-serine in the brain. In addition, it would also be of interest to investigate how brain levels of Land D-serine can affect blood levels of amino acids associated with the NMDA receptors. In the present study, we used an automated blood sampling system to examine whether intracerebroventricular (icv) infusion of Land Dserine can alter the plasma levels of amino acids (glutamate, glutamine, glycine, L-serine, and D-serine) in conscious and freely moving rats. MATERIALS AND METHODS