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.

阿尔茨海默氏病患者的证据表明基础 前脑胆碱能系统在记忆中起重要作用。 支持 在此提案中，我们发现了视觉识别记忆受损 具有该系统主要核病变的猕猴，正常 猴子管理胆碱能毒蕈碱蛋白酶阻滞剂 scopolamine。 保留的另一种形式，空间记忆也受损 通过scopolamine，尽管它比识别记忆更具抵抗力。 我们的结果还表明，scopolamine会影响主要，而不是 只是次要内存和内存存储，而不是检索。 与众不同 西pol碱在不到3秒的延迟下发挥最大作用， 四氢大麻酚（THC）仅在超过延迟时损害刺激记忆 30秒。 这表明THC不是通过 胆碱能系统，实际上是在麻醉中使用体内微透析 猴子，我们发现THC增加了乙酰胆碱的释放 在第一个但不随后的管理部门上的海马，表明 该乙酰胆碱储存尚未耗尽。 猴子管理 多巴胺能神经毒素MPTP最初表现出运动和习惯 在几周内解决的形成障碍后来发现 对西pol碱的影响异常敏感，表明残留 损害多巴胺能系统。 这是通过正电子排放确认的 断层扫描和体内微透析，两者均显示多巴胺降低 尾状核，壳核和前额叶皮层的水平。 动物 随后发现弯路能力受损， 空间内存。 在进一步测试新教学在学习中的作用，我们 发现视觉系统的新纹状体目标的破坏（即 尾状核和尾腹壳的尾巴产生了严重的 在测试习惯形成的测试中受损，但没有在认知记忆中。 到 研究滥用药物的加强作用所涉及的机制， 我们将卡马西平施用到猴子自我管理可卡因和 发现前一个药物大大降低了每日摄入量 后者。