NEURAL SUBSTRATES OF LEARNING DEFICIT DUE TO PCP ABUSE

这项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 中枢神经系统中的底物。行为，神经化学， 生物物理方法将被用来检测潜在的细胞 五氯苯酚导致学习障碍的机制。五氯苯酚，一种常见的街头毒品 滥用，是NMDA离子载体的非竞争性拮抗者 受体。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 将评估五氯苯酚对学习、记忆及其潜在的影响 神经机制。我们将在中使用的眨眼条件调节任务 兔子有直接的行为，可能还有神经上的相似之处 人类。将使用的PCP剂量方案试图模拟 五氯酚滥用者的消费模式。我们假设激活了 NMDA受体复合体对联想学习至关重要，基于 我们的发现是，慢性PCP治疗阻碍了获取。保留 以前学习的任务也将进行测试。PCP与高密度脂蛋白结合 NMDA受体离子载体内的亲和力，特别致密 结合集中在海马区。我们建议测试一下 海马区是五氯苯酚有害作用的底物 学习，使用两个海马体依赖的任务，跟踪和音调 兔辨别反转眨眼条件反射。MK-801绑定 与NMDA离子载体内的PCP受体结合具有较高的亲和力 而且比PCP本身更具特异性。我们有初步证据 眨眼条件作用导致[~3H]MK-801结合增强(An 全海马膜制剂中Bmax)的增加。 与假条件下或处理过的对照兔进行了对比训练。我们 将通过检查PCP的影响来重复和扩展这些实验 [~3H]MK-801结合及与之相关的时程增强结合 具体的学习阶段和PCP治疗的具体时间表。 将使用定量放射自显影技术来确定 是否存在细胞内结合改变的特异性 条件化和/或PCP治疗后的海马体。慢的 后超极化(AHP)，钙依赖的kappa+电导(S)， 这是在海马CA1区锥体细胞动作电位爆发之后出现的 学习后细胞减少。五氯苯酚显然也会影响特定的 卡帕+电导。AHP的变化，在尖峰调节和在 学习诱导并受PCP影响的特定kappa~+电导 将在带有电流和电压钳位的CA1锥体细胞中进行评估 切片/补丁准备中的录制。五氯苯酚和/或 关于NMDA介导的传播的学习也将被审查。我们的 设计了一项实验计划来表征行为缺陷 滥用五氯苯酚的原因，以及开始调查原因 细胞水平的因子与生物物理和神经化学 技巧。由于五氯苯酚是一种主要的滥用药物，很可能这 研究计划可以对以下方面做出相当直接的贡献 理解并可能改善学习缺陷，这可能会 是五氯苯酚滥用的主要后果。

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.