PHARMACOLOGY OF COGNITIVE MEMORY AND HABIT FORMATION

认知记忆和习惯形成的药理学

• 批准号: 3859874
• 负责人: T G AIGNER
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3859874
• 关键词: Alzheimer's disease; Macaca; acetylcholine; aging; anticholinergic agent; brain mapping; brain metabolism; cannabinoids; carbamazepine; choline inhibitor; cholinergic agents; cocaine; cognition; dopamine; experimental brain lesion; habits; hippocampus; memory; memory disorders; methylphenyltetrahydropyridine; microdialysis; molecular psychobiology; neuroanatomy; neurotoxins; physostigmine; positron emission tomography; psychopharmacology; reinforcer; scopolamine; space perception; visual cortex

Evidence from patients with Alzheimer's disease suggests that the basal forebrain cholinergic system plays an important role in memory. In support of this proposal, we have found impaired visual recognition memory in macaques with lesions of the major nuclei of this system, and in normal monkeys administered the cholinergic muscarinic-receptor blocker scopolamine. Another form of retention, spatial memory, is also impaired by scopolamine, although it is more resistant than is recognition memory. Our results suggest, in addition, that scopolamine affects primary, not just secondary memory, and memory storage, not retrieval. Unlike scopolamine, which exerts maximal effects at delays of less than 3 seconds, tetrahydrocannabinol (THC) impairs stimulus memory only at delays exceeding 30 seconds. This suggests that THC is not exerting its effect via the cholinergic system and, indeed, using in vivo microdialysis in anesthetized monkeys, we found that THC increased acetylcholine release in the hippocampus on the first but not subsequent administrations, indicating that acetylcholine stores had not been depleted. Monkeys administered the dopaminergic-neurotoxin MPTP, who initially showed motor and habit formation impairments that resolved within a few weeks, were found later to be abnormally sensitive to the effects of scopolamine, suggesting residual damage to the dopaminergic system. This was confirmed by positron emission tomography and in vivo microdialysis, both of which showed reduced dopamine levels in caudate nucleus, putamen, and prefrontal cortex. The animals were subsequently found to have impaired detour reaching ability and spatial memory. In further tests of a neostriatal role in learning, we found that destruction of the visual system's neostriatal targets (i.e., tail of caudate nucleus and caudoventral putamen) produced severe impairment on a test of habit formation, but none in cognitive memory. To study the mechanisms involved in the reinforcing effects of drugs of abuse, we administered carbamazepine to monkeys self-administering cocaine and found that the former drug significantly decreased the daily intake of the latter.

来自阿尔茨海默病患者的证据表明，基础 前脑胆碱能系统在记忆中起着重要作用。 支持中 根据这个提议，我们发现视觉识别记忆受损 该系统主要核损伤的猕猴，以及正常的猕猴 给猴子注射胆碱能毒蕈碱受体阻滞剂 东莨菪碱。 另一种形式的保留，即空间记忆，也受到损害 东莨菪碱虽然比识别记忆更具有抵抗力。 此外，我们的结果表明，东莨菪碱影响原发性，而不是影响原发性。 只是辅助记忆和记忆存储，而不是检索。 不像 东莨菪碱在延迟不到3秒的时间内发挥最大效果， 四氢大麻酚 (THC) 仅在延迟超过时才会损害刺激记忆 30秒。 这表明 THC 并不是通过 胆碱能系统，事实上，在麻醉中使用体内微透析 在猴子身上，我们发现 THC 增加了乙酰胆碱的释放 海马体在第一次而不是随后的给药中出现，表明 乙酰胆碱储备尚未耗尽。 猴子管理 多巴胺能神经毒素 MPTP，最初表现出运动和习惯 形成障碍在几周内得到解决，后来发现 对东莨菪碱的作用异常敏感，表明残留 多巴胺能系统受损。 正电子发射证实了这一点 断层扫描和体内微透析，均显示多巴胺减少 尾状核、壳核和前额皮质的水平。 动物们 随后被发现绕道到达能力受损 空间记忆。 在进一步测试新纹状体在学习中的作用时，我们 发现视觉系统的新纹状体目标被破坏（即 尾状核尾部和尾腹壳核）产生了严重的 习惯形成测试有障碍，但认知记忆没有障碍。 到 研究涉及滥用药物的强化作用的机制， 我们给猴子服用卡马西平并自行服用可卡因 发现前一种药物显着减少了每天的摄入量 后者。