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.

项目摘要/摘要 苯丙胺型刺激剂（ATS），例如甲基苯丙胺（甲基）（甲基苯丙胺）是高度添加剂，是 世界上第二大的非法药物。即使美国的ATS生产大大增加了 兴奋剂的使用仍然是重要的公共卫生，财务和法律问题，没有可靠的 由于对脑电路的了解有限，治疗ATS的药物治疗（AUD） AUD的基础及其复杂的作用机制。尽管许多AT会增加两个大脑 去甲肾上腺素（NE）和多巴胺（DA），对NE转运蛋白（NET）的亲和力高于DA 转运蛋白，对中央电路作为潜在治疗目标的作用的关注得多 aud。最近的临床前研究和临床研究突出了NE在质末端的床核中 （BNST）是滥用药物，戒断和压力引起的药物恢复原状的重要贡献 寻求。腹侧（V）BNST中的NE传播，主要起源于固体的核 区域（NST），来自奖励和压力相关的刺激的综合信息，并介导随后的行为 回答。但是，关于NST-NE- vbnst途径在AUD中的隐含以及它是如何的，知之甚少 由于方法论局限 解剖学上的小/复杂和神经化学上异质的BNST。此外，BNST是性的 女性的二态二态且体积要小得多（人类的2.5倍）比男性小，但对 NST-NE的性别差异vbnst系统及其对AUD的影响。 该提案的目标1将（i）确定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）表征甲基对NST NE调节的影响 NE系统与应力诱导的行为变化的相关性。 AIM 2将确定 NST-NE- VBNST途径在应激诱导的甲基甲基寻求的动物模型中的功能作用 （复发/渴望）通过化学上的甲基化范例调节该途径。 为了实现这些目标，我们提出了一种使用快速扫描循环的创新和集成的方法 NST-NE投影神经元对野生型大鼠的VBNST的伏安法和化学作用调节。这 研究将填补我们对NST-NE- VBNST途径及其对NST-NE的理解的重要空白及其对 甲基苯丙胺引起的神经化学和行为变化及其独特的性别差异的慢性影响。 这些结果将提供有关ATS使用的潜在神经生物学机制的见解，并可能导致 使用性别特定治疗策略对AUD的新疗法。