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

项目摘要/摘要 苯丙胺类兴奋剂(AT)，如甲基苯丙胺(冰毒)具有高度成瘾性，是 世界上使用第二多的非法药物。尽管ATS在美国的产量大幅增加 兴奋剂的使用仍然是一个重要的公共卫生、金融和法律问题，没有得到证实的 由于对大脑回路的有限了解，治疗ATS使用障碍(AUD)的药物疗法 潜在的澳元及其复杂的作用机制。尽管许多安非他明类兴奋剂增加了两个大脑 去甲肾上腺素(NE)和多巴胺(DA)，与NE转运体(Net)的亲和力高于DA 作为转运体，中央NE环路作为潜在治疗靶点的作用受到的关注要少得多 澳元。最近的临床前和临床研究强调了终纹床核的去甲肾上腺素 (BNST)是药物滥用、戒断和压力诱导的药物恢复的重要贡献者 寻找。NE在腹侧(V)BNST的传递，主要起源于孤束核 途径(NST)，整合来自奖赏和压力相关刺激的信息，并调节随后的行为 回应。然而，Nst-NEvBNST通路是如何参与AUD的，以及它是如何参与AUD的，我们知之甚少 在选择性研究去甲肾上腺素时由于方法学的限制而导致的行为改变。 BNST在解剖上很小/复杂，在神经化学上是不同的。此外，BNST是性方面的 雌性的体积比雄性小得多(人类的体积比雄性小2.5倍)，但人们对此知之甚少 Nst-NEvBNST系统的性别差异及其对AUD的影响 该提案的目标1将(I)确定Nst-NEvBNST的解剖学和神经化学差异 雄性和雌性大鼠之间的系统和(II)冰毒对NST中去甲肾上腺素调节的影响 VBNST以及NE系统与应激诱导的行为改变的相关性。目标2将决定 Nst-NEvBNST通路在应激性寻冰动物模型中的功能作用 (复发/渴求)在冰毒自我给药范例中通过化学方式调节这一途径。 为了实现这些目标，我们提出了一种创新的综合方法，利用快速扫描循环 野生型大鼠NST-NE投射神经元对vBNST的伏安和化学调制这 研究将填补我们对Nst-NEvBNST途径及其贡献的一个重要空白 冰毒所致神经化学和行为改变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洞察，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.