Distinct contributions of glutamate and dopamine receptors to temporal aspects of rodent working memory using a clinically relevant task
Distinct contributions of glutamate and dopamine receptors to temporal aspects of rodent working memory using a clinically relevant task
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DOI：
10.1007/s002130000590
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发表时间：
2001-01-01
影响因子：
3.4
通讯作者：
Moghaddam, B
中科院分区：
文献类型：
--
作者：
Aultman, JM;Moghaddam, B
理论基础：了解工作记忆的机制基础，即在线持有表征的能力，对于描绘涉及高级认知功能的过程和思维障碍的病理生理学非常重要。目的：我们比较了谷氨酸和多巴胺受体亚型对工作记忆时间方面的贡献，使用了一种改进的啮齿动物空间工作记忆任务，该任务结合了临床工作记忆任务的重要元素。方法：采用离散配对试验可变延迟T迷宫任务。初步的特征研究表明，这项任务的表现在数秒长的保持间隔内是稳定的，对保持间隔和主动干扰很敏感，并依赖于内侧前额叶皮质的完整性。结果：与临床研究结果一致的是，小剂量苯丙胺(0.25 mg/kg)可产生延迟依赖性的表现改善，而高剂量则损害所有保留间隔的表现。阻断D1R可产生可预测的剂量和延迟依赖的损伤。D2受体阻断剂不起作用。前额叶皮质中的代谢性谷氨酸2/3(mGluR2/3)受体的激活抑制了谷氨酸的缓慢异步期释放，也产生了延迟依赖性的损害。低剂量的AMPA/海人藻酸受体拮抗剂的作用与mGluR2/3激动剂相似。相反，NMDA受体拮抗剂诱导的损伤是记忆负荷不敏感的，导致在所有保留间隔的机会水平的表现。结论：NMDA受体的激活对记忆编码的形成是必需的，而调节成分包括谷氨酸的缓慢非同步释放和多巴胺的时相释放有助于信息在延迟期的主动维持。
Rationale: Understanding the mechanistic basis of working memory, the capacity to hold representation "on line," is important for delineating the processes involved in higher cognitive functions and the pathophysiology of thought disorders. Objectives: We compared the contribution of glutamate and dopamine receptor subtypes to temporal aspects of working memory using a modified rodent spatial working memory task that incorporates important elements of clinical working memory tasks. Methods: A discrete paired-trial variable-delay T-maze task was used. Initial characterization studies indicated that performance on this task is stable at seconds-long retention intervals, is sensitive to retention interval and proactive interference, and is dependent on the integrity of the medial prefrontal cortex. Results: Consistent with clinical findings, low dose amphetamine (0.25 mg/kg) produced a delay-dependent improvement in performance, while higher doses impaired performance at all retention intervals. D1 receptor blockade produced the predicted dose- and delay-dependent impairment. D2 receptor blockade had no effect. Activation of metabotropic glutamate 2/3 (mGluR2/3) receptors, which in the prefrontal cortex inhibits the slow asynchronous phase of glutamate release, also produced a delay-dependent impairment. Low doses of an AMPA/kainate antagonist had effects similar to the mGluR2/3 agonist. In contrast, NMDA receptor antagonist-induced impairment was memory load-insensitive, resulting in chance-level performance at all retention intervals. Conclusions: These findings suggest that activation of NMDA receptors is necessary for the formation of mnemonic encoding while modulatory components involving slow asynchronous release of glutamate and phasic release of dopamine contribute to the active maintenance of information during the delay period.