OPIOIDS AND THE PHYSIOLOGY OF THE VENTRAL PALLIDUM

阿片类药物与腹侧苍白球的生理学

• 批准号: 2700823
• 负责人: T. Celeste Napier
• 金额: $ 17.56万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 2000-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2700823
• 关键词: G protein; behavioral habituation /sensitization; central neural pathway /tract; dopamine; electrophysiology; endogenous opioid; gene induction /repression; immunocytochemistry; laboratory rat; lenticular nucleus; limbic system; morphine; neural transmission; neuropharmacology; nontherapeutic iontophoresis; nucleus accumbens; opioid receptor; regulatory gene; tegmentum

The ventral pallidum (VP) may be a neurobiological substrate for the motivational aspects of opiate addiction, such as drug craving. Though grossly understudied, the neural adaptations that underlie the enhanced responding that occurs after repeated exposure to opiates likely parallel those mediating drug craving in the addict. Chronic opiates appear to induce long lasting changes in the ventral tegmental area (VTA) and the nucleus accumbens (NA). We hypothesize that VP neurons undergo a persistent adaptation to chronic opiate exposure. This may reflect an alteration in VTA and NA inputs, as well as changes in VP neurons themselves. To test these hypotheses, biochemical and electrophysiological comparisons will be made among these regions in rats that demonstrate morphine-induced sensitization. Specific Aim 1. To determine which aspects of the opioid receptor-mediated signal transduction system are involved in neuronal adaptations to chronic morphine treatments. Alterations in signal transduction may be critical mechanisms by which the brain adapts to chronic exposure to drugs of abuse. The effects of morphine-induced sensitization will be examined by this Aim by measuring G protein levels, adenylyl cyclase activity and immediate early gene induction. The results should indicate the biochemical underpinnings of functional changes seen in Aims 2 and 3. Specific Aim 2. To determine the ability of chronic morphine treatments to alter responses of VP and NA neurons to opioid agonists and antagonists. The opioid receptors that mediate morphine-induced sensitization and the physiological parallels to changes in opioid receptor-effector coupling seen during this sensitization are not known. Experiments in Aim 2 will use extracellular electrophysiology in combination with microiontophoretic application of opioid receptor subtype-specific drugs to provide the first examination of these issues for the VP and NA. Specific Aim 3. To determine if chronic morphine treatments alter opioid modulation of dopaminergic transmission from the VTA to the VP and NA. With extracellular electrophysiology, we recently revealed that opioids modulate dopamine transmission in the VP. As neuromodulation can occur on membrane events that are subthreshold to the generation of an action potential, intracellular recordings of VP and NA neurons in vivo will be used to determine if chronic morphine alters this modulation. Because the VP serves as a major output for the mesolimbic system, studies on this region are critical to understanding the consequences of neural adaptations of the brain's reward system. The proposed experiments should provide new insights for the development of more efficacious therapy for compulsive drug use and craving.

腹侧苍白球（VP）可能是阿片成瘾动机方面（例如药物渴望）的神经生物学基础。 尽管尚未得到充分研究，但反复接触阿片类药物后反应增强的神经适应可能与成瘾者调节药物渴望的神经适应相似。 慢性阿片类药物似乎会引起腹侧被盖区（VTA）和伏隔核（NA）的长期持续变化。 我们假设 VP 神经元对长期阿片类药物暴露进行持续的适应。 这可能反映了 VTA 和 NA 输入的变化，以及 VP 神经元本身的变化。 为了检验这些假设，将对大鼠的这些区域进行生化和电生理学比较，以证明吗啡诱导的致敏作用。具体目标 1. 确定阿片受体介导的信号转导系统的哪些方面参与神经元对长期吗啡治疗的适应。 信号转导的改变可能是大脑适应长期接触滥用药物的关键机制。 该目标将通过测量 G 蛋白水平、腺苷酸环化酶活性和立即早期基因诱导来检查吗啡诱导的致敏作用。 结果应表明目标 2 和 3 中所见功能变化的生化基础。 具体目标 2. 确定长期吗啡治疗改变 VP 和 NA 神经元对阿片类激动剂和拮抗剂反应的能力。 介导吗啡诱导的致敏作用的阿片受体以及在致敏过程中观察到的阿片受体-效应器耦合变化的生理学平行情况尚不清楚。 目标 2 中的实验将使用细胞外电生理学与阿片受体亚型特异性药物的微离子电渗疗法相结合，为 VP 和 NA 提供对这些问题的首次检查。具体目标 3. 确定长期吗啡治疗是否会改变阿片类药物对从 VTA 到 VP 和 NA 的多巴胺能传输的调节。 通过细胞外电生理学，我们最近发现阿片类药物可调节 VP 中的多巴胺传递。 由于神经调节可能发生在动作电位产生阈值以下的膜事件上，因此体内 VP 和 NA 神经元的细胞内记录将用于确定慢性吗啡是否会改变这种调节。由于 VP 是中脑边缘系统的主要输出，因此对该区域的研究对于理解大脑奖励系统神经适应的后果至关重要。拟议的实验应该为开发更有效的药物强迫使用和渴望疗法提供新的见解。