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

Zhi-Qiang Liu; Xun-Hu Gu; Yuan-Jian Yang; Xiao-ping Yin; Li-Jun Xu; Wei Wang

doi:10.1016/j.pbb.2016.02.002

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

Pharmacol Biochem Behav. 2016 Apr:143:44-56. doi: 10.1016/j.pbb.2016.02.002. Epub 2016 Feb 6.

Authors

Zhi-Qiang Liu¹, Xun-Hu Gu², Yuan-Jian Yang³, Xiao-ping Yin⁴, Li-Jun Xu⁵, Wei Wang⁶

Affiliations

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.

PMID: 26861675
DOI: 10.1016/j.pbb.2016.02.002

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.

Keywords: Behavioral sensitization; Cocaine; Conditioned place preference; Nucleus accumbens; d-Serine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Behavior, Animal*
Chromatography, High Pressure Liquid
Cocaine / administration & dosage
Cocaine-Related Disorders / metabolism
Cocaine-Related Disorders / physiopathology
Conditioning, Classical*
Dose-Response Relationship, Drug
Male
Nucleus Accumbens / metabolism*
Rats
Rats, Sprague-Dawley
Serine / metabolism*

Substances

Serine
Cocaine