OPIOIDS AND THE PHYSIOLOGY OF THE VENTRAL PALLIDUM

腹侧苍白球（VP）可能是阿片成瘾动机方面的神经生物学基础，如药物渴望。然而，到目前为止，慢性阿片类药物暴露对副总统生理的影响尚未探讨。在反复间歇性暴露于阿片类药物的大鼠中，在增强的行为反应中发生的神经适应可能与成瘾者中介导药物渴望的神经适应相似。慢性阿片类药物似乎诱导腹侧被盖区（VTA）和伏隔核（NA）的持久变化。我们假设VP神经元也经历了对慢性阿片类药物暴露的持续适应。我们还提出，这反映了VTA和NA输入的改变，以及VP神经元本身的变化。为了验证这些假设，将对表现出吗啡诱导行为致敏的大鼠进行NA和VP的电生理比较。具体目标确定慢性吗啡治疗改变VP和NA神经元对阿片激动剂和拮抗剂反应的能力。介导吗啡致敏的阿片受体以及与这些变化的生理相似之处尚不清楚。Aim 1的实验将使用细胞外电生理学结合阿片受体亚型特异性药物的微离子电泳应用，为VP和NA提供这些问题的第一次检查。具体目标2。确定慢性吗啡治疗是否改变阿片调节多巴胺能从VTA到VP和NA的传递。通过细胞外电生理学，我们最近发现阿片类药物调节副脑内多巴胺的传递。由于神经调节可以发生在动作电位产生的阈下膜事件上，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。慢性吗啡治疗改变了NA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，本研究将采用与Aim 1相同的治疗模式，进行实验，以确定慢性吗啡治疗是否会改变阿片类药物调节多巴胺传递的能力。由于副脑区是中边缘系统的主要输出区，因此对该区域的研究对于理解大脑奖励系统的神经适应后果至关重要。提出的实验应该为开发更有效的治疗强迫性药物使用和渴望提供新的见解。

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.