d-Serine in the nucleus accumbens region modulates behavioral sensitization and extinction of conditioned place preference

• Systematically evaluate the role of the d-serine on addiction behaviors.
• d-serine blocks behavioral sensitization by inhibition of ERK-CREB-Fos pathway and reversing the cocaine-induced decrease of NR2B.
• d-serine participates in the induction of LTD through a NMDAR glycine site-dependent mechanism.

Backgroundd-serine, the endogenous co-agonist of N-methyl-d-aspartate receptors (NMDARs), is considered to be essential for learning and memory. The aim of the current investigation was to systematically evaluate the role of d-serine on addiction behaviors considered to be mediated by the nucleus accumbens (NAc).Methodsd-Serine concentration in the NAc was measured by high-performance liquid chromatography (HPLC). Cocaine-induced behavioral sensitization and conditioned place preference (CPP) models were used to evaluate the relation between changes in serine in the nucleus accumbens and cocaine-induced behavioral effects. The expression of serine racemase (SR), D-amino acid oxidase (DAAO), the cAMP response element-binding protein (CREB) and upstream kinases, and N-methyl-d-aspartate (NMDA) receptors subunits were analyzed by western blot. Long-term depression (LTD) in the NAc was investigated by electrophysiological methods.ResultsThe NAc slices obtained from the behavioral sensitization rats presented significantly reduced d-serine concentrations, increased expression of DAAO, and down-regulated expression of SR in a dose-dependent manner. Furthermore, d-serine injections into the nucleus accumbens blocked the development of behavioral sensitization and caused extinction of CPP. The ERK-CREB-Fos pathway and the NMDA receptor NR2B subunits in the NAc were involved in the cocaine-induced behavioral sensitization. We also found that d-serine was essential for NMDAR-dependent LTD and d-serine-regulated LTD in a bell-shaped concentration-dependent manner. The disrupted NMDAR-dependent LTD in the NAc of cocaine-treated rats was reversed by d-serine.ConclusionsOur results provide evidence for a critical role of d-serine in synaptic plasticity relevant to cocaine addiction and indicate that d-serine may be an effective therapeutic agent for cocaine addiction.