NEURAL SUBSTRATES OF LEARNING DEFICIT DUE TO PCP ABUSE

PCP 滥用导致学习缺陷的神经基础

• 批准号: 3214323
• 负责人: JOHN F DISTERHOFT
• 金额: $ 18.96万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-12-15 至 1995-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3214323
• 关键词: NMDA receptors; PCP receptor; action potentials; association learning; autoradiography; computer data analysis; conditioning; drug abuse; experimental brain lesion; eye movement disorders; hippocampus; ion transport; ionophores; laboratory rabbit; learning disorders; memory disorders; neural transmission; neurochemistry; phencyclidine; pyramidal cells; receptor binding; voltage /patch clamp

This proposal describes a series of experiments designed to investigate the effects of phencyclidine (PCP) on associative learning and its substrates in the central nervous system. Behavioral, neurochemical, and biophysical methods will be used to examine potential cellular mechanisms for PCP-induced learning deficits. PCP, a common street drug of abuse, is a noncompetitive antagonist of the ionophore of the NMDA receptor. The NMDA channel has received considerable attention recently because of its involvement in the induction of neural plasticity. We will assess the effects of PCP on learning, memory, and its underlying neural mechanisms. The eyeblink conditioning task we will use in rabbits has direct behavioral, and presumably neural, parallels in humans. The PCP dose regimens to be used attempt to simulate the consumption patterns of PCP abusers. We hypothesize that activation of the NMDA receptor-complex is critical for associative learning, based on our finding that chronic PCP treatment blocks acquisition. Retention of previously learned tasks will also be tested. PCP binds with high affinity within the NMDA receptor's ionophore, with particularly dense binding concentrated in the hippocampus. We propose to test whether the hippocampus is a substrate for PCP's observed deleterious effects on learning, using two hippocampally-dependent tasks, trace and tone discrimination reversal eyeblink conditioning in rabbits. MK-801 binds to the PCP receptor site within the NMDA ionophore with higher affinity and greater specificity than PCP itself. We have preliminary evidence that eyeblink conditioning causes enhanced [3H]MK-801 binding (an increase in Bmax) in whole hippocampal membrane preparations from trained compared to pseudoconditioned or handled control rabbits. We will repeat and extend these experiments by examining the effects of PCP on [3H]MK-801 binding, and the time course enhanced binding related to specific stages of learning and specific schedules of PCP treatment. Quantitative autoradiographic techniques will be used to determine whether there is cellular specificity of altered binding within hippocampus following conditioning and/or PCP treatment. The slow afterhyperpolarization (AHP), a Ca2+-dependent kappa+ conductance(s), that follows a burst of action potentials in hippocampal CA1 pyramidal cells is reduced after learning. PCP also apparently affects specific kappa+ conductances. Changes in the AHP, in spike accommodation and in specific kappa+ conductances induced by learning and affected by PCP will be evaluated in CA1 pyramidal cells with current-and voltage-clamp recordings in the slice/patch preparation. Effects of PCP and/or learning on NMDA-mediated transmission will also be examined. Our experimental program is designed to characterize the behavioral deficits which PCP abuse causes, as well as to begin to investigate causative factors at the cellular level with biophysical and neurochemical techniques. Since PCP is a major drug of abuse, it is likely that this research program could make a rather direct contribution to understanding and possibly ameliorating the learning deficits which may be a major consequence of PCP abuse.

该提案描述了一系列旨在研究 苯环利定对联想学习的影响及其机制 在中枢神经系统中的作用 行为学神经化学， 生物物理学方法将用于检查潜在的细胞 PCP诱导的学习障碍的机制。 PCP，一种常见的街头毒品 是NMDA离子载体的非竞争性拮抗剂， 受体的 NMDA通道最近受到了相当大的关注 因为它参与了神经可塑性的诱导。 我们 将评估PCP对学习，记忆及其潜在的影响。 神经机制。 眨眼条件反射任务，我们将使用在 兔子有直接的行为，大概是神经， 人类 拟使用的五氯苯酚剂量方案试图模拟 五氯苯酚滥用者的消费模式。 我们假设， NMDA受体复合体对联想学习至关重要， 我们发现慢性五氯酚治疗阻止了获得。 保留 以前学习的任务也将被测试。 五氯苯酚与高浓度 NMDA受体的离子载体内的亲和力，特别是密集 结合集中在海马体。 我们建议测试 海马体是五氯苯酚所观察到的有害作用的基质， 学习，使用两个依赖于训练的任务，跟踪和音调 辨别反转眨眼条件反射。 MK-801结合 与NMDA离子载体内的PCP受体位点具有更高的亲和力 比五氯苯酚本身的特异性更强 我们有初步证据 眨眼条件反射导致[3 H]MK-801结合增强（ Bmax的增加）的整个海马膜制备物 与假条件或处理的对照兔相比。 我们 将通过检验五氯苯酚的影响来重复和扩展这些实验 对[3 H]MK-801结合的影响，以及与 具体的学习阶段和具体的五氯苯酚治疗时间表。 定量放射自显影技术将用于确定 是否有细胞特异性改变结合内 海马体后调节和/或PCP治疗。 缓慢 后超极化（AHP），钙依赖性κ +电导（s）， 海马CA 1区锥体细胞动作电位爆发后 学习后细胞减少。 五氯苯酚显然还影响特定的 kappa+电导。 在层次分析法的变化，在穗住宿和 学习诱导的和PCP影响的比κ +电导 将在CA 1锥体细胞中用电流钳和电压钳进行评价 切片/贴片制备中的记录。 五氯苯酚和/或 还将研究关于NMDA介导的传播的学习。 我们 实验程序的目的是表征行为缺陷 以及开始调查 细胞水平的生物物理和神经化学因素 技术. 由于五氯苯酚是一种主要的滥用药物， 研究计划可以做出相当直接的贡献， 了解并可能改善学习缺陷， 是滥用五氯酚的主要后果。