OPIOIDS AND THE PHYSIOLOGY OF THE VENTRAL PALLIDUM

腹侧苍白球(VP)可能是阿片成瘾的激励因素的神经生物学底物，如对药物的渴求。然而，到目前为止，慢性阿片类药物暴露对VP生理的影响还没有被探索。在反复间歇性接触阿片类药物引起的行为反应增强过程中，发生的神经适应很可能与介导吸毒者对药物的渴望的神经适应类似。慢性阿片类药物似乎会导致腹侧被盖区(VTA)和伏隔核(NA)的长期变化。我们假设，VP神经元也经历了对长期阿片类药物暴露的持续适应。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。为了验证这些假说，我们将对表现出吗啡诱导的行为敏感化的大鼠进行NA和VP的电生理学比较。具体目的1.确定慢性吗啡处理改变VP和NA神经元对阿片激动剂和拮抗剂的反应的能力。介导吗啡诱导敏化的阿片受体以及这些变化的生理相似之处尚不清楚。目标1中的实验将使用细胞外电生理学结合阿片受体亚型特定药物的微离子导入，为VP和NA提供这些问题的第一次检查。具体目的2.确定慢性吗啡治疗是否改变阿片类药物对多巴胺能传递的调节，使其从VTA传递到VP和NA。通过细胞外电生理学，我们最近发现阿片类药物调节了多巴胺在VP中的传递。由于神经调节可以发生在动作电位产生的阈值下的膜事件上，因此将进行活体细胞内VP和NA神经元的记录，以评估吗啡改变这些参数的能力。慢性吗啡治疗后，NA中的多巴胺能传递发生改变。然而，这种变化的生理基础还没有被探索。因此，使用与目标1相同的治疗模式，将进行这一目标的实验，以确定慢性吗啡治疗是否改变阿片剂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的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治疗强迫性药物使用和渴求的方法提供新的见解。

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.