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: 2120124
• 负责人: JOHN F DISTERHOFT
• 金额: $ 17.7万
• 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/2120124
• 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.

这个建议描述了一系列旨在调查的实验