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

终纹-去甲肾上腺素系统床核在安非他明类兴奋剂使用障碍中的作用

• 批准号: 10660048
• 负责人: Jinwoo Park
• 金额: $ 65.44万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660048
• 关键词: Abstinence; Acute; Adrenergic Agents; Affinity; Amphetamines; Anatomy; Animal Model; Attention; Attenuated; Autoreceptors; Behavior; Behavioral; Brain; Brain Stem; Cell Nucleus; Cells; Chemosensitization; Chronic; Clinical Research; Cocaine; Complex; Data; Dopamine; Dose; Drug user; Exhibits; Female; Genetic; Goals; Human; Legal; Locomotion; Mediating; Methamphetamine; Methodology; Neurons; Norepinephrine; Nucleus solitarius; Outcome; Pathway interactions; Pattern; Periodicity; Pharmaceutical Preparations; Pharmacotherapy; Predisposition; Production; Public Health; Rattus; Regulation; Relapse; Rewards; Role; Scanning; Self Administration; Sex Differences; Signal Transduction; Stimulant; Stimulus; Stress; Structure; Structure of terminal stria nuclei of preoptic region; Substance abuse problem; System; Time; Up-Regulation; Withdrawal; addiction; anxiety-like behavior; behavioral response; biological adaptation to stress; craving; dopamine transporter; drug abstinence; drug seeking behavior; extracellular; hypothalamic-pituitary-adrenal axis; illicit drug use; in vivo; innovation; insight; male; mesolimbic system; methamphetamine effect; methamphetamine exposure; methamphetamine use; nerve supply; neuroadaptation; neurobiological mechanism; neurochemistry; neurotransmission; new therapeutic target; noradrenaline transporter; norepinephrine system; novel therapeutics; preclinical study; presynaptic; psychostimulant; response; sensory stimulus; sex; sexual dimorphism; stimulant abuse; stimulant dependence; stimulant use; stimulant use disorder; stimulant user; stressor; success; therapeutic target; transmission process; treatment strategy

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.

项目概要/摘要 安非他明类兴奋剂 (ATS)，例如甲基苯丙胺 (METH)，具有高度成瘾性，是 世界上使用量第二大的非法药物。尽管美国的苯丙胺类兴奋剂产量急剧增加 兴奋剂的使用仍然是一个重要的公共卫生、财务和法律问题，但尚无证据证明 由于对大脑回路的了解有限，治疗 ATS 使用障碍 (AUD) 的药物疗法 潜在的 AUD 及其复杂的作用机制。尽管许多 ATS 都会增加大脑 去甲肾上腺素 (NE) 和多巴胺 (DA)，与 NE 转运蛋白 (NET) 的亲和力高于 DA 转运蛋白，但人们对中枢 NE 回路作为潜在治疗靶点的作用的关注要少得多 澳元。最近的临床前和临床研究强调了终纹床核中的 NE （BNST）是药物滥用、戒断和压力诱导的药物恢复的重要因素 寻求。腹侧 (v)BNST 中的 NE 传输，主要源自孤立核 道（NST），整合来自奖励和压力相关刺激的信息并介导后续行为 回应。然而，关于 NST-NE vBNST 通路如何与 AUD 相关以及它如何发挥作用，人们知之甚少。 由于选择性研究 NE 的方法学限制，导致行为改变 解剖学上小/复杂且神经化学异质的 BNST。此外，BNST 在性方面 雌性比雄性具有二态性，体积小得多（人类小 2.5 倍），但人们对它知之甚少 NST-NE vBNST 系统中的性别差异及其对 AUD 的影响。 该提案的目标 1 将 (i) 识别 NST-NEvBNST 中的解剖学和神经化学差异 雄性和雌性大鼠之间的系统，以及（ii）表征 METH 对 NST 中 NE 调节的影响 和 vBNST 以及 NE 系统与压力引起的行为变化的相关性。目标 2 将决定 NST-NEvBNST 通路在应激诱导的 METH 寻求动物模型中的功能作用 （复发/渴望）通过在冰毒自我管理范式中化学遗传学调节该途径。 为了实现这些目标，我们提出了一种利用快速扫描循环的创新和综合方法 野生型大鼠中 NST-NE 投射神经元到 vBNST 的伏安法和化学遗传学调节。这 研究将填补我们对 NST-NEvBNST 通路及其贡献的理解的重要空白 冰毒引起的神经化学和行为变化的慢性影响及其明显的性别差异。 这些结果将深入了解苯丙胺类兴奋剂使用的潜在神经生物学机制，并可能导致 使用性别特异性治疗策略治疗 AUD 的新疗法。