Zhi-Qiang Liu1, Xun-Hu Gu2, Yuan-Jian Yang3, Xiao-ping Yin4, Li-Jun Xu5, Wei Wang6. 1. Department of Neurology, Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China; Cadre of Neurology, Jiangxi People's Hospital, Nanchang, Jiangxi, China; Department of Medical Experimental Center, Jiangxi Mental Hospital, Nanchang, Jiangxi, China. 2. Department of Neurology, Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China; Department of Medical Experimental Center, Jiangxi Mental Hospital, Nanchang, Jiangxi, China. 3. Department of Medical Experimental Center, Jiangxi Mental Hospital, Nanchang, Jiangxi, China. 4. Department of Neurology, Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China. 5. Department of Neurology, Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China. Electronic address: xulijun20050901@sina.com. 6. Department of Neurology, Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China. Electronic address: wuhansy@126.com.
Abstract
BACKGROUND: D-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). METHODS: D-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. RESULTS: The 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. CONCLUSIONS: Our 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.
BACKGROUND:D-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). METHODS:D-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. RESULTS: The 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. CONCLUSIONS: Our 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.