Stress-Induced Alterations in Amygdala-LC Interactions

药物滥用是当今社会的主要有害影响，压力是药物滥用中最突出的诱发风险因素之一。众所周知，压力会影响许多系统;但在药物滥用和压力中起重要作用的一个系统是多巴胺（DA）系统。然而，压力如何影响DA系统一直有些争议，在神经化学研究通常表明，压力诱导的增加中脑边缘DA系统，而电生理学研究更常见的报告压力诱导的抑制DA神经元。我们已经发现，不同的应激类型可以有显着不同的影响DA神经元的活动。因此，尽管急性伤害性刺激将暂时抑制单个DA神经元，但维持强应激源（例如重复的足电击或束缚应激）将增加DA神经元放电的数量（即，群体活动），导致DA系统对其他刺激的高反应性。相比之下，慢性不可避免的冷应激或约束应激后24小时的测试导致DA神经元群体活性和对苯丙胺的行为反应的有效降低。此外，这些变化在内侧（即，奖励相关的）-横向（即，腹侧被盖区（VTA）及其相关的小脑投射部位的显著性相关）范围，这可能具有重要的功能意义。因此，约束应力增加DA神经元的人口活动的内侧-外侧腹侧被盖区轴，而反复足电击增加，慢性冷减少，人口活动只在内侧腹侧被盖区。此外，这些压力源显示出强有力的相互作用，暴露于慢性冷应激“保护”外侧DA系统免受约束的影响。在本建议中，我们将研究 一系列已知激活或减弱DA系统的应激源如何影响腹侧被盖区内外侧范围内的DA神经元群体活动。我们将评估参与这一过程的电路，我们的初步结果表明，海马腹侧下托参与应激诱导的DA神经元活动增加和基底外侧杏仁核应激诱导的DA神经元活动减少。这些研究解决了我们的中心假设：压力源的类型决定其对DA系统和药物滥用的影响，与激活和抑制DA系统的反应性调节在腹侧被盖区的区域特定的方式由特定的传入途径。这将按照沿着4个目标进行：1）测试每种应激源如何影响DA神经元活动和苯丙胺诱导的运动，2）测试腹侧下托和基底外侧杏仁核如何影响DA系统中的应激诱导的变化，3）测试先前暴露于DA衰减应激源如何影响对激活应激源的DA能反应，和4）检查DA激活与衰减应激源如何影响安非他明自我给药。这些研究应该提供重要的见解，不同的压力如何影响DA系统，这种相互作用的机制，反过来，它们将如何影响滥用药物的倾向，并提供新的治疗方法的见解。

DESCRIPTION (provided by applicant): Drug abuse is a major detrimental influence on society today, and stress is among the most prominent predisposing risk factors in drug abuse. Stress is known to affect a number of systems; but one system that plays a prominent role in both drug abuse and stress is the dopamine (DA) system. However, how stress affects the DA system has been somewhat controversial, in that neurochemical studies typically show stress-induced increases in mesolimbic DA systems, whereas electrophysiological studies more commonly report stress-induced inhibition of DA neurons. We have found that different stressor types can have markedly different effects on DA neuron activity. Thus, although acute noxious stimuli will transiently suppress individual DA neurons, maintained strong stressors such as repeated footshock or restraint stress will increase the number of DA neurons firing (i.e., population activity), leading to a hyper-responsivity of the DA system to other stimuli. In contrast, chronic inescapable cold stress or testing 24 hours after a restraint stress leads to a potent decrease in DA neuron population activity and the behavioral response to amphetamine. Moreover, these changes occur differentially across the medial (i.e., reward-related) -lateral (i.e., salience-related) extent of the ventral tegmental area (VTA) and its associated accumbens projection sites, which likely will have important functional implications. Thus, restraint stress increases DA neuron population activity across the medial-lateral VTA axis, whereas repeated footshock increase, and chronic cold decreases, population activity exclusively in the medial VTA. Moreover, these stressors show potent interactions, with exposure to chronic cold stress "protecting" the lateral DA system from the effects of restraint. In this proposal, we will examine how a range of stressors known to activate or attenuate the DA system affect DA neuron population activity across the medial-lateral extent of the VTA. We will assess the circuits involved in this process, which our preliminary results suggest that the ventral subiculum of the hippocampus is involved in stress-induced increases and the basolateral amygdala in stress-induced decreases in DA neuron activity. These studies address our central hypothesis: The type of stressor determines its impact on the DA system and drug abuse liability, with activation and suppression of DA system responsivity regulated in a VTA regionally-specific manner by specific afferent pathways. This will be done along 4 aims: 1) Test how each stressor affects DA neuron activity and amphetamine-induced locomotion, 2) Test how the ventral subiculum and the basolateral amygdala impact the stress-induced changes in the DA system, 3) Test how prior exposure to DA-attenuating stressors impact the DAergic response to activating stressors, and 4) examine how DA activating versus attenuating stressors affect amphetamine self-administration. These studies should provide important insights into how different stressors affect the DA system, the mechanisms underlying this interaction and, in turn, how they would impact the propensity to abuse drugs and provide insight into novel therapeutic approaches.