Sex Differences in Addiction

成瘾的性别差异

• 批准号: 10546585
• 负责人: Amy Kohtz
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10546585
• 关键词: Abstinence; Address; Animal Model; Automobile Driving; Basic Science; Behavior; Behavioral; Behavioral Model; Bioinformatics; Biological; Clinical Research; Clinical Treatment; Cocaine; Complex; Dependence; Development; Dorsal; Drug Addiction; Drug Targeting; Drug usage; Electrophysiology (science); Extinction (Psychology); Face; Faculty; Female; Gene Expression Profile; Gene Targeting; Genes; Goals; Hippocampus (Brain); Home; Human; Institution; Intervention; Link; Maintenance; Maintenance Therapy; Methods; Molecular Profiling; Neuronal Plasticity; Neurons; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacogenetics; Phase; Population; Positioning Attribute; Pre-Clinical Model; Rattus; Recovery; Relapse; Research; Resistance; Risk; Rodent; Rodent Model; Role; Sex Behavior; Sex Differences; Signal Pathway; Signal Transduction; Substance Use Disorder; Techniques; Testing; Time; Trademark; Training; Transcript; Woman; addiction; awake; biological adaptation to stress; cocaine exposure; cocaine self-administration; conditioned place preference; craving; designer receptors exclusively activated by designer drugs; drug abstinence; drug of abuse; drug seeking behavior; drug standard; effective therapy; experimental study; functional genomics; locus ceruleus structure; male; men; neural circuit; neural recruitment; neuroregulation; new therapeutic target; noradrenergic; novel; programs; promoter; psychologic; recruit; relapse prediction; relating to nervous system; resilience; response; sex; substance abuse treatment; success; tenure track; therapeutic target; transcriptome; transcriptome sequencing

Project Summary/Abstract. The inability to maintain abstinence is a trademark of addiction yet effective maintenance therapies remain elusive. Women may face unique issues with substance abuse treatment, as research indicates that psychological and biological responses to drugs of abuse differ in women compared to men. Women tend to show greater drug dependence, progress more quickly from casual drug use to dependence, have greater difficulty quitting, and have shorter periods of abstinence than men. These effects have been similarly observed in female animal models. Thus, there is a crucial need for understanding circuit dynamics and molecular signatures that drive robust behavioral sex differences impeding abstinence success. We have developed a novel behavioral model termed the seeking-persistence paradigm (SPP) that was adapted from standard drug abstinence paradigms. The seeking-persistence paradigm is used to investigate the influence of intervention during initial abstinence on long-term drug-seeking behaviors. Indeed, cocaine-seeking during initial abstinence strongly correlates with seeking after drug-abstinence. These results reflect clinical studies indicating that craving during initial abstinence predicts relapse rates. Using this paradigm in combination with electrophysiological, chemogenetic, and functional genomic methods, we aim to ultimately provide novel targets for therapeutics by investigating the role of sex-specific signaling in driving cocaine seeking persistence. We have previously identified that the dorsal hippocampus CA1 is a crucial downstream target for noradrenergic (NE) modulation of cocaine-seeking on ED1. Notably, the locus coeruleus (LC) (NE)-CA1 signal in this behavior appears female- specific, and we hypothesize that recruitment of this pathway engages increased cocaine-seeking observed in females. In year 1 of the K99 phase, I will first determine if this sex difference involves phasic or tonic locus coeruleus firing on ED1 using unit recordings in behaving rats. In year 2 of the K99 phase, I will use RNA- sequencing and bioinformatics analyses to identify a molecular signature in CA1 of increased cocaine-seeking behavior. Next, in my independent phase (R00) I will combine prior training in chemogenetic techniques with new training in awake behaving electrophysiology to identify the effects of inhibition or activation of LC inputs to dorsal hippocampus CA1 on ED1 cocaine seeking and cocaine seeking-persistence, using PRSx8 promoter driven designer receptors exclusively activated by designer drugs (DREADDs) that permit specific expression in LC-NE neurons. Subsequently, I will use my bioinformatics training to identify clusters of transcripts that associate with cocaine-seeking resilience by examining transcripts that negatively correlate to cocaine-seeking behavior. These experiments will therefore characterize the role of the LC(NE)-CA1 pathway in driving cocaine- seeking behavior and identify novel gene targets in CA1 associated with sex differences in cocaine-seeking. The ultimate goal of this research is to identify the behavioral significance of neural activity (Aim 1), activated transcripts (Aim 2), and recruited circuits (Aim 3) driving sex differences in cocaine-seeking SPP.

项目摘要/摘要。 无法维持禁欲是成瘾的标志，但维持疗法却是有效的 仍然难以捉摸。研究表明，女性在药物滥用治疗方面可能面临独特的问题 与男性相比，女性对滥用药物的心理和生物反应有所不同。女性倾向于 表现出更大的药物依赖，从随意吸毒到依赖的进展更快，有更大的 戒烟困难，并且戒烟时间比男性短。这些影响也被类似地观察到 在雌性动物模型中。因此，迫切需要了解电路动力学和分子 导致严重行为性别差异的特征阻碍了禁欲成功。我们开发了一个 新颖的行为模型，称为寻求持久范式（SPP），改编自标准药物 禁欲范式。使用寻求-坚持范式来研究干预的影响 在最初戒除长期吸毒行为期间。事实上，在最初戒断期间寻求可卡因 与寻求戒毒密切相关。这些结果反映了临床研究表明渴望 在最初的戒断期间可以预测复发率。使用这种范例与电生理学相结合， 化学遗传学和功能基因组方法，我们的目标是最终通过以下方式提供新的治疗靶标 研究性别特异性信号在驱动可卡因寻求持久性方面的作用。我们之前有过 确定背侧海马 CA1 是去甲肾上腺素能 (NE) 调节的重要下游靶点 在 ED1 上寻找可卡因。值得注意的是，这种行为中的蓝斑 (LC) (NE)-CA1 信号似乎是女性- 具体而言，我们假设该途径的募集会增加在 女性。在 K99 阶段的第一年，我将首先确定这种性别差异是否涉及阶段性或强直性基因座 Coeruleus 使用行为大鼠的单位记录对 ED1 进行放电。在 K99 阶段的第二年，我将使用 RNA- 测序和生物信息学分析可识别 CA1 中可卡因寻求增加的分子特征 行为。接下来，在我的独立阶段 (R00)，我将把之前的化学遗传学技术培训与 清醒行为电生理学的新训练，以确定 LC 输入的抑制或激活的影响 使用 PRSx8 启动子，背侧海马 CA1 对 ED1 可卡因寻求和可卡因寻求持久性的影响 驱动的设计受体专门由设计药物（DREADD）激活，允许在 LC-NE 神经元。随后，我将利用我的生物信息学训练来识别转录本簇 通过检查与可卡因寻求负相关的转录本，将其与可卡因寻求弹性联系起来 行为。因此，这些实验将表征 LC(NE)-CA1 途径在驱动可卡因- 寻求行为并识别 CA1 中与可卡因寻求性别差异相关的新基因目标。这 这项研究的最终目标是确定神经活动的行为意义（目标 1），激活 转录本（目标 2）和招募回路（目标 3）驱动可卡因寻求 SPP 中的性别差异。