Dysfunction of glutamate neurotransmission in the nucleus accumbens (NAc) has been implicated in the pathophysiology of alcohol use disorders (AUD). Neurogranin (Ng) is exclusively expressed in the brain and mediates N‐methyl‐d‐aspartate receptor (NMDAR) hypo‐function by regulating the intracellular calcium‐calmodulin (Ca²⁺‐CaM) pathway. Ng null mice (Ng^–/– mice) demonstrate increased alcohol drinking compared to wild‐type mice, while also showing less tolerance to the effect of alcohol. To identify the molecular mechanism related to alcohol seeking, both in vivo microdialysis and label‐free quantification proteomics comparing Ng genotype and effects of alcohol treatment on the NAc are utilized. There is significant difference in glutamate and gamma‐aminobutyric acid (GABA) neurotransmission between genotypes; however, alcohol administration normalizes both glutamate and GABA levels in the NAc. Using label‐free proteomics, 427 protein expression changes are identified against alcohol treatment in the NAc among 4347 total proteins detected. Bioinformatics analyses reveal significant molecular differences in Ng null mice in response to acute alcohol treatment. Ingenuity pathway analysis found that the AKT network is altered significantly between genotypes, which may increase the sensitivity of alcohol in Ng null mice. The pharmacoproteomics results presented here illustrate a possible molecular basis of the alcohol sensitivity through Ng signaling in the NAc.

中文翻译：

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Neurogranin通过伏隔核中的AKT途径调节酒精敏感性。

伏伏核（NAc）的谷氨酸神经传递功能障碍与酒精使用障碍（AUD）的病理生理有关。神经颗粒素（Ng）仅在大脑中表达，并通过调节细胞内钙钙调蛋白（Ca ²⁺ -CaM）途径介导N-甲基-d-天门冬氨酸受体（NMDAR）功能低下。Ng空小鼠（Ng ^{– / –}与野生型小鼠相比，小鼠饮酒量增加，同时对酒精作用的耐受性也降低。为了确定与寻求酒精有关的分子机制，利用了体内微透析和比较Ng基因型以及酒精处理对NAc的影响的无标记定量蛋白质组学。基因型之间的谷氨酸和γ-氨基丁酸（GABA）神经传递存在显着差异。但是，酒精管理可以使NAc中的谷氨酸和GABA含量均正常化。使用无标记蛋白质组学，在NAc中检测到的4347种总蛋白中，针对酒精处理鉴定出427种蛋白表达变化。生物信息学分析显示，Ng无效小鼠对急性酒精治疗有明显的分子差异。创造力途径分析发现，基因型之间的AKT网络发生了显着变化，这可能会增加Ng缺失小鼠中酒精的敏感性。此处给出的药代动力学结果说明了通过NAc中Ng信号传导进行酒精敏感性检测的可能分子基础。