Aultman J M, Moghaddam B
Department of Psychiatry, Yale University School of Medicine, VA Medical Center, West Haven, CT 06516, USA.
Psychopharmacology (Berl). 2001 Jan;153(3):353-64. doi: 10.1007/s002130000590.
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.
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.
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.
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.
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.
理解工作记忆（即“在线”保持表征的能力）的机制基础，对于描绘高级认知功能所涉及的过程以及思维障碍的病理生理学至关重要。
我们使用一种改良的啮齿动物空间工作记忆任务，该任务纳入了临床工作记忆任务的重要元素，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。
使用离散配对试验可变延迟T迷宫任务。初步特征研究表明，该任务的表现在数秒长的保持间隔内是稳定的，对保持间隔和前摄干扰敏感，并且依赖于内侧前额叶皮质的完整性。
与临床发现一致，低剂量苯丙胺（0.25毫克/千克）产生了延迟依赖性的表现改善，而高剂量在所有保持间隔下均损害表现。D1受体阻断产生了预期的剂量和延迟依赖性损害。D2受体阻断没有效果。代谢型谷氨酸2/3（mGluR2/3）受体的激活，其在前额叶皮质中抑制谷氨酸释放的缓慢异步阶段，也产生了延迟依赖性损害。低剂量的AMPA/海人藻酸拮抗剂具有与mGluR2/3激动剂相似的作用。相比之下，NMDA受体拮抗剂诱导的损害对记忆负荷不敏感，导致在所有保持间隔下的表现处于随机水平。
这些发现表明，NMDA受体的激活对于记忆编码的形成是必要的，而涉及谷氨酸缓慢异步释放和多巴胺阶段性释放的调节成分有助于在延迟期内对信息的主动维持。
