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: 6041709
• 负责人: T. Celeste Napier
• 金额: $ 4.48万
• 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 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6041709
• 关键词: action potentials; central neural pathway /tract; chloral hydrate; dopamine; drug addiction; drug withdrawal; endogenous opioid; immunocytochemistry; laboratory rat; lenticular nucleus; morphine; naloxone; neuropharmacology; nucleus accumbens; opioid receptor; tegmentum

The ventral pallidum (VP) may be a neurobiological substrate for the motivational aspects of opiate addiction, such as drug craving. To date, however, the effects of chronic opiate exposure on the physiology of the VP have not been explored. The neural adaptations that occur during the enhanced behavioral responding that is induced by repeated intermittent exposure to opiates in rats 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 also undergo a persistent adaptation to chronic opiate exposure. We also pose that this reflects an alteration in VTA and NA inputs, as well as changes in VP neurons themselves. To test these hypotheses, electrophysiological comparisons will be made between the NA and VP to rats that demonstrate morphine-induced behavioral sensitization. Specific Aim 1. 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 these changes are not known. Experiments in Aim 1 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 2. 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 conducted to evaluate ability of morphine to alter these parameters. Dopaminergic transmission is altered in the NA with chronic morphine treatments. However, the physiological underpinnings of this change have not been explored. Thus, using the same treatment paradigm as that employed in Aim 1, experiments in this Aim will be conducted to determine if chronic morphine treatments alter the ability of the opiate to modulate dopamine transmission. 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。 然而，迄今为止，尚未探讨长期阿片类药物暴露对 VP 生理学的影响。 大鼠反复间歇性接触阿片类药物所引起的行为反应增强期间发生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 神经元也会对长期阿片类药物暴露进行持续的适应。 我们还认为这反映了 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，将在 NA 和 VP 之间与大鼠进行电生理学比较，以证明吗啡诱导的行为敏化。 具体目标 1. 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与这些变化的生理相似性尚不清楚。 目标 1 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 2. 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，因此将进行体内 VP 和 NA 神经元的细胞内记录，以评估吗啡改变这些参数的能力。 长期吗啡治疗会改变 NA 中的多巴胺能传递。 然而，这种变化的生理基础尚未被探索。 因此，使用与目标 1 中采用的相同的治疗范例，将进行该目标中的实验以确定长期吗啡治疗是否改变阿片类药物调节多巴胺传递的能力。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。