Stress-Induced Alterations in Amygdala-LC Interactions

描述(申请人提供)：药物滥用是当今社会的主要有害影响，压力是药物滥用最突出的诱因之一。众所周知，压力会影响许多系统；但在药物滥用和压力中扮演重要角色的一个系统是多巴胺系统。然而，应激如何影响DA系统一直存在一定的争议，因为神经化学研究通常显示应激诱导的中脑边缘DA系统的增加，而电生理学研究更多地报告应激诱导的DA神经元的抑制。我们发现，不同的应激源类型对DA神经元的活动有明显不同的影响。因此，尽管急性伤害性刺激会暂时抑制单个DA神经元，但持续的强烈应激源，如重复的足电击或束缚应激，会增加DA神经元的放电数量(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束缚应激后24小时的测试会导致DA神经元群体活动和对苯丙胺的行为反应显著减少。此外，这些变化在腹侧被盖区(VTA)的内侧(即奖赏相关)-外侧(即突显相关)范围及其相关的伏隔投射部位发生的差异很可能具有重要的功能意义。因此，束缚应激增加了横跨VTA内侧轴的DA神经元群体活动，而反复足电击增加，慢性寒冷减少，群体活动仅在VTA内侧。此外，这些应激源表现出很强的相互作用，暴露在慢性冷应激中“保护”外侧DA系统免受束缚的影响。在这份提案中，我们将研究 已知的激活或减弱DA系统的一系列应激源如何影响VTA内侧-外侧区的DA神经元群体活动。我们将评估参与这一过程的回路，我们的初步结果表明，海马腹下丘参与了应激诱导的增加，而杏仁基底外侧核参与了应激诱导的DA神经元活性的降低。这些研究解决了我们的中心假设：应激源的类型决定了它对DA系统和药物滥用易感性的影响，通过特定的传入通路以VTA区域特有的方式调节DA系统反应性的激活和抑制。这将沿着4个目标进行：1)测试每个应激源如何影响DA神经元的活动和苯丙胺诱导的运动；2)测试腹侧下丘和杏仁基底外侧核如何影响应激诱导的DA系统的变化；3)测试先前暴露于DA衰减应激源如何影响DA能对激活应激源的反应；以及4)检查DA激活和减弱应激源如何影响苯丙胺自我给药。这些研究应该为不同的应激源如何影响DA系统、这种相互作用背后的机制以及它们将如何影响滥用药物的倾向提供重要的见解，并为新的治疗方法提供洞察。

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.