Baseline-dependent enhancement of working memory by memantine in male rats: Involvement of NMDA receptor subunits and CaMKII signaling

IF 3.3 3区心理学 Q1 BEHAVIORAL SCIENCES

Pharmacology Biochemistry and Behavior Pub Date : 2024-11-08 DOI:10.1016/j.pbb.2024.173904

Shuo-Fu Chen , Wan-Ju Cheng , Chih-Chang Chao , Chun-Hsien Kuo , Ruey-Ming Liao

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引用次数: 0

Abstract

N-methyl-d-aspartate (NMDA) receptors, activated by glutamate, play a crucial role in learning and memory. Memantine (MEM), a non-competitive NMDA receptor antagonist, is currently prescribed for the treatment of Alzheimer's disease or dementia, which meanwhile simultaneously promotes a need to clarify its potential pro-cognitive effects that exist in normal healthy individuals. However, the neurobehavioral mechanisms underlying the cognitive improvement by MEM in normal individuals remain to be elucidated. This study aimed to assess the effects of MEM on working memory, measured by a discrete paired-trial delay alternation task in a T-maze in normal male rats. The impacts of MEM were hypothesized to vary depending on different baseline levels of working memory performance. Neurochemical examination of the levels of calcium/calmodulin-dependent kinase 2 (CaMKII) and NMDA receptor subunits within five targeted brain regions was conducted after behavioral tests. The results showed that acute administration of MEM enhanced working memory performance, with 2.5, 5.0, and 10 mg/kg doses increasing task accuracy compared to the vehicle, particularly in low performers. Neurochemically, the protein expression of CaMKII in the amygdala and that of the glutamate (Glu) N2A subunit in the dorsal striatum were greater in the low-performance group than in the high-performance group. Additionally, the protein expression of the GluN2A subunit in the dorsal striatum was negatively associated with task performance at baseline. The expression of GluN1 and GluN2B in the nucleus accumbens was negatively associated with task performance in the retest three weeks after drug treatment. These findings underscore the baseline-dependent improvement of working memory resulting from MEM administration, with observed drug effects associated with alterations in the levels of NMDA receptor subunits in striatal subareas and CaMKII in the amygdala.

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美金刚对雄性大鼠工作记忆的基线依赖性增强：NMDA 受体亚基和 CaMKII 信号转导的参与。

由谷氨酸激活的 N-甲基-d-天冬氨酸（NMDA）受体在学习和记忆中起着至关重要的作用。美金刚（MEM）是一种非竞争性的 NMDA 受体拮抗剂，目前被用于治疗阿尔茨海默病或痴呆症，与此同时，人们也需要弄清它对正常健康人的潜在认知促进作用。然而，MEM 改善正常人认知能力的神经行为机制仍有待阐明。本研究旨在评估 MEM 对正常雄性大鼠工作记忆的影响，其测量方法是在 T 型迷宫中进行离散配对试验延迟交替任务。根据假设，MEM 的影响会因工作记忆能力的不同基线水平而异。行为测试结束后，对五个目标脑区的钙/钙调蛋白依赖性激酶2（CaMKII）和NMDA受体亚基水平进行了神经化学检测。结果表明，急性给药 MEM 可提高工作记忆能力，2.5、5.0 和 10 毫克/千克剂量的 MEM 可提高任务准确性，与给药车辆相比尤其如此。从神经化学角度看，低能组杏仁核中CaMKII的蛋白表达量和背侧纹状体中谷氨酸（Glu）N2A亚基的蛋白表达量均高于高能组。此外，背侧纹状体中 GluN2A 亚基的蛋白表达与基线任务表现呈负相关。在药物治疗三周后的复测中，凹凸核中 GluN1 和 GluN2B 的表达与任务表现呈负相关。这些发现强调了 MEM 对工作记忆改善的基线依赖性，观察到的药物效应与纹状体亚区 NMDA 受体亚单位和杏仁核 CaMKII 水平的改变有关。

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来源期刊

Pharmacology Biochemistry and Behavior 医学-行为科学

CiteScore

6.40

自引率

2.80%

发文量

122

审稿时长

38 days

期刊介绍： Pharmacology Biochemistry & Behavior publishes original reports in the areas of pharmacology and biochemistry in which the primary emphasis and theoretical context are behavioral. Contributions may involve clinical, preclinical, or basic research. Purely biochemical or toxicology studies will not be published. Papers describing the behavioral effects of novel drugs in models of psychiatric, neurological and cognitive disorders, and central pain must include a positive control unless the paper is on a disease where such a drug is not available yet. Papers focusing on physiological processes (e.g., peripheral pain mechanisms, body temperature regulation, seizure activity) are not accepted as we would like to retain the focus of Pharmacology Biochemistry & Behavior on behavior and its interaction with the biochemistry and neurochemistry of the central nervous system. Papers describing the effects of plant materials are generally not considered, unless the active ingredients are studied, the extraction method is well described, the doses tested are known, and clear and definite experimental evidence on the mechanism of action of the active ingredients is provided.