D-serine Of The Nucleus Accumbens Region Modulates Cocaine Addiction Behavior

Objective:Drug addiction is an enduring psychiatric illness characterized by compulsive drug craving, seeking, and ingestion despite severe adverse consequences. Yet the potential brain mechanisms are not well understood. The aim of the current investigation is to evaluate the concentrations of D-serine in the behavioral sensitization and the effect and mechanism of D-serine to addiction behavior.Method:In order to establish behavioral sensitization models, different concentrations of cocaine(5, 15, 25mg/kg) were injected intraperitoneally(i.p.) into SD rats once daily for six consecutive days, then rats were kept in their home cages for 14-day withdrawal. On test day, all rats were given i.p. injections of cocaine(15 mg/kg).D-serine concentrations in NAc obtained from cocaine-treated rats were measured by High-performance liquid chromatography(HPLC). Systemic administration exogenous D-serine( 10,30,100mg/kg) or intra-NAc infusion of exogenous D-serine(2, 5μg/perside) 1 hour before an injection of cocaine on test day to inhibit drug-seeking behavior. Expression of serine racemase(SR), D-amino acid oxidase(DAAO), the c AMP response element-binding protein(CREB), the extracellular signal-regulated kinase(ERK1/2) and calcium/calmodulin-dependent kinases II(CAMKII) were analyzed by Western blot. The mechanisms of D-serine in NAc region of normol and behavioral sensitization rats modulated NMDAR-LTD were investigated by electrophysiological methods.Results:We found that D-serine concentrations in NAc obtained from behavioral sensitization rats presented significantly reduced[one-way ANOVA; F(3,20) = 40.64;P ﹤0.01]. SR, synthetase of D-serine, expression significantly decreased[one-way ANOVA; F(3,20) = 23.18; P ﹤ 0.01]and DAAO, catabolic enzyme of D-serine,expression significantly increased[one-way ANOVA; F(3,20) = 25.44; P ﹤ 0.01].Systemic administration and intra-NAc infusion of different concentrations ofexogenous D-serine blocked the development of behavioral sensitization in a dose-dependent manner[one-way ANOVA; F(3,44) = 33.65, P < 0.01; F(3,20) =13.25,P < 0.01; respectively]. Western blot showed p CREB and p ERK1/2 levels significantly increased in NAc of behavioral sensitization rats(P < 0.05),but Ca MKII phosphorylation levels did not show any significant effects after drug administration(P ﹥ 0.05). And electrophysiological methods showed that D-serine was essential for NMDAR-LTD in NAc and exogenous D-serine regulated NMDAR-LTD in a bell-shaped concentration-dependent manner. We also found that NMDAR-LTD in NAc was disrupted of chronic cocaine-treated rats.Conclusion:The D-serine deficit observed in NAc of cocaine-treated rats is likely due to the altered amount of key enzyme.Exogenous D-serine blocks the development of behavioral sensitization, so, D-serine may be an effective therapeutic agent for cocaine addiction.The ERK-CREB-Fos pathway involves in cocaine-induced behavioral sensitization.NMDAR-LTD of cortico-accumbal glutamatergic synapse is disrupted in chronic cocaine-treated rats and reversed by D-serine.