The Role of the Bed Nucleus of the Stria Terminalis-Norepinephrine System in Amphetamine-type Stimulant Use Disorders

项目总结/摘要 苯丙胺类兴奋剂（ATS），如甲基苯丙胺（METH），具有很强的成瘾性， 世界上第二大非法药物。尽管美国的安非他明类兴奋剂产量大幅增加， 和兴奋剂的使用仍然是一个重要的公共卫生，财政和法律的问题，没有证明 由于对大脑回路的了解有限， 潜在的AUD及其复杂的作用机制。虽然许多ATS增加了大脑 去甲肾上腺素（NE）和多巴胺（DA），并且对NE转运体（NET）的亲和力高于DA 作为一种转运蛋白，中枢NE回路作为治疗的潜在靶点的作用受到的关注要少得多 的AUD。最近的临床前和临床研究强调NE在终纹床核 （BNST）作为药物滥用，戒断和压力诱导的药物复吸的重要贡献者 寻找NE在腹侧（v）BNST的传递，主要来自孤束核 神经束（NST）整合来自奖励和压力相关刺激的信息，并介导随后的行为 应答然而，很少有人知道NST-NE β vBNST通路是如何参与AUD的，以及它是如何影响AUD的。 由于在选择性研究NE中的方法学限制， 解剖学上小/复杂和神经化学上异质的BNST。此外，BNST在性方面 雌性比雄性体积小得多（人类体积小2.5倍），但对雄性的了解甚少。 NST-NE-BNST系统的性别差异及其对AUD的影响。 本提案的目的1将（i）确定NST-NE神经元和BNST的解剖学和神经化学差异 系统之间的雄性和雌性大鼠和（ii）表征的影响METH对NE调节NST 和vBNST以及NE系统与应激诱导的行为变化的相关性。目标2将决定 NST-NE介导的BNST通路在应激诱导的METH寻求动物模型中的功能作用 通过在METH自我给药范例中化学遗传学地调节该途径来抑制（复发/渴望）。 为了实现这些目标，我们提出了一种创新的和综合的方法，利用快速扫描循环 伏安法和NST-NE投射神经元对野生型大鼠vBNST的化学发生调节。这 这项研究将填补我们对NST-NE β vBNST通路及其对 甲基苯丙胺引起的神经化学和行为变化的慢性效应及其明显的性别差异。 这些结果将提供对ATS使用的潜在神经生物学机制的深入了解，并可能导致 使用性别特异性治疗策略治疗AUD的新疗法。

PROJECT SUMMARY/ABSTRACT Amphetamine-type stimulants (ATS), such as methamphetamine (METH) are highly addictive and are the second most used illicit drugs in the world. Even though ATS production in the US has dramatically increased and stimulant use remain an important public health, financial, and legal issue, there are no proven pharmacotherapies to treat ATS use disorders (AUD) due to a limited understanding of the brain circuits underlying AUD and their complex mechanisms of action. Although many ATS increase both brain norepinephrine (NE) and dopamine (DA), and have higher affinities for the NE transporter (NET) than the DA transporter, far less attention has been paid to the role of central NE circuits as a potential target for treatment of AUD. Recent preclinical and clinical studies have highlighted NE in the bed nucleus of the stria terminalis (BNST) as an important contributor to substance abuse, withdrawal, and stress-induced reinstatement of drug seeking. NE transmission in the ventral (v)BNST, which primarily originates from the nucleus of the solitary tract (NST), integrates information from reward and stress related stimuli and mediates subsequent behavioral responses. However, little is known about how the NST-NE vBNST pathway is implicated in AUD and how it contributes to behavioral changes due to methodological limitations in selectively studying NE in the anatomically small/complex and neurochemically heterogeneous BNST. Furthermore, the BNST is sexually dimorphic and much smaller in volume (2.5X less for humans) in females than males, yet little is known about sex differences in the NST-NE vBNST system and its effect on AUD. Aim 1 of this proposal will (i) identify anatomical and neurochemical differences in the NST-NEvBNST system between male and female rats and (ii) characterize the effects of METH on NE regulation in the NST and vBNST and the correlation of the NE system with stress-induced behavioral changes. Aim 2 will determine the functional role of the NST-NEvBNST pathway in animal models of stress-induced METH seeking (relapse/craving) by chemogenetically modulating this pathway in METH self-administration paradigms. To achieve these Aims, we propose an innovative and integrative approach utilizing fast-scan cyclic voltammetry and chemogenetic modulation of NST-NE projection neurons to the vBNST in wild-type rats. This study will fill an important gap in our understanding of the NST-NEvBNST pathway and its contributions to the chronic effects of METH-induced neurochemical and behavioral changes and its distinct sex differences. These results will provide insight into the underlying neurobiological mechanisms of ATS use and may lead to novel therapeutics for of AUD using sex specific treatment strategies.