Sex Differences in Endocannabinoid Regulation of Behavioral Flexibility

内源性大麻素对行为灵活性调节的性别差异

• 批准号: 10606290
• 负责人: Catherine A. Stapf
• 金额: $ 4.01万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-13 至 2026-01-12
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606290
• 关键词: Affect; Automobile Driving; Behavior; Behavioral; Brain; CNR1 gene; Cells; Chronic; Clinical; Clinical Research; Corpus striatum structure; Cue-induced relapse; Cues; Data; Development; Disease; Dorsal; Drug Exposure; Drug usage; Electrophysiology (science); Endocannabinoids; Equilibrium; Female; Food; Genetic; Genetic Transcription; Glutamates; Goals; Human; Impairment; Individual; Individual Differences; Interneurons; Mediating; Messenger RNA; Modeling; Molecular; Motivation; Neurobiology; Neurons; Outcome; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Population; Probability; Rattus; Receptor Activation; Receptor Signaling; Regulation; Relapse; Reporting; Research; Rewards; Rodent; Sex Differences; Slice; Substance Use Disorder; Synapses; Testing; Vulnerable Populations; Woman; addiction; brain circuitry; cocaine craving; cocaine relapse; cocaine use; craving; cue reactivity; drug of abuse; drug relapse; endocannabinoid signaling; experience; experimental study; flexibility; gamma-Aminobutyric Acid; mRNA Expression; male; men; neurotransmitter release; optogenetics; patch clamp; pre-clinical; preclinical study; presynaptic; prevent; sex; transmission process; Affect; Automobile Driving; Behavior; Behavioral; Brain; CNR1 gene; Cells; Chronic; Clinical; Clinical Research; Corpus striatum structure; Cue-induced relapse; Cues; Data; Development; Disease; Dorsal; Drug Exposure; Drug usage; Electrophysiology (science); Endocannabinoids; Equilibrium; Female; Food; Genetic; Genetic Transcription; Glutamates; Goals; Human; Impairment; Individual; Individual Differences; Interneurons; Mediating; Messenger RNA; Modeling; Molecular; Motivation; Neurobiology; Neurons; Outcome; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Population; Probability; Rattus; Receptor Activation; Receptor Signaling; Regulation; Relapse; Reporting; Research; Rewards; Rodent; Sex Differences; Slice; Substance Use Disorder; Synapses; Testing; Vulnerable Populations; Woman; addiction; brain circuitry; cocaine craving; cocaine relapse; cocaine use; craving; cue reactivity; drug of abuse; drug relapse; endocannabinoid signaling; experience; experimental study; flexibility; gamma-Aminobutyric Acid; mRNA Expression; male; men; neurotransmitter release; optogenetics; patch clamp; pre-clinical; preclinical study; presynaptic; prevent; sex; transmission process

Project Summary Around 30% of individuals who try drugs of abuse transition to addiction, suggesting that individual differences prior to drug experience contribute to addiction vulnerability. Sign-tracking and goal-tracking phenotypes which predict distinct drug relapse vulnerabilities, have been modelled in humans and rodents. Sign-tracking rats show enhanced cue sensitivity prior to drug experience which predicts heightened cue-driven drug seeking and increased cue-induced relapse as compared to goal-trackers. Men and women also differ in their addiction vulnerability, where women show enhanced escalation of drug use and higher probability to relapse. Female rats are more likely to be sign-trackers, suggesting a need to study sex differences in sign-tracking rats to understand the unique neurobiological vulnerabilities in females. Sign-trackers and females are similarly inflexible when rewarding outcomes are devalued. I have found that decreasing cannabinoid 1 receptors (CB1R) signaling in the dorsomedial striatum (DMS) makes female sign-tracking rats flexible, but has the opposite effect in male sign-tracking rats. CB1R are expressed on orbitofrontal cortex (OFC) inputs to the DMS and on GABAergic interneurons and medium spiny neurons in the DMS. This project will focus on the intersection of sex and sign-tracking, investigating DMS endocannabinoid regulation of behavioral flexibility. I hypothesize that a CB1R-mediated decrease in OFC-DMS transmission prevents flexibility in female sign- tracking rats, while a CB1R-mediated decrease in GABAergic transmission promotes flexibility of male sign- tracking rats. First, I will use slice electrophysiology and RNAscope to understand the functional and expression-based differences in CB1R within the DMS between male and female ST rats. Second, I will use chemogenetics and slice electrophysiology to investigate the contribution of OFC-DMS projection to behavioral flexibility and the influence of CB1R activation on this projection. Through these experiments, I aim to uncover critical molecular and circuit-based mechanisms that contribute to impairments in flexibility that are associated with addiction vulnerability.

项目摘要 约有30％的人尝试过渡到成瘾的毒品，这表明个体差异 在吸毒之前，会导致成瘾脆弱性。签名跟踪和目标跟踪表型 预测在人类和啮齿动物中已经建模了明显的药物复发脆弱性。签名跟踪大鼠 在药物体验之前显示提高提示灵敏度，这可以预测提示驱动的药物寻求和 与目标跟踪者相比，提示引起的复发增加。男人和女人的成瘾也有所不同 脆弱性，妇女表现出增强的药物使用升级和复发的可能性更高。女性 大鼠更有可能是签名者，这表明需要研究签名跟踪大鼠的性别差异 了解女性中独特的神经生物学脆弱性。签名者和女性类似 当奖励成果贬值时，不灵活。我发现降低大麻素1受体 （CB1R）背侧纹状体（DMS）中的信号传导使女性签名跟踪大鼠柔性，但具有 男性签名跟踪大鼠的相反作用。 CB1R在轨道额皮层（OFC）输入到DMS上表示 在DMS中的GABA能中间神经元和中刺神经元上。这个项目将重点放在 性别和标志跟踪的交集，研究了DMS内源性大麻素的行为灵活性调节。我 假设CB1R介导的OFC-DMS传播的降低可防止女性签名的灵活性 跟踪大鼠，而CB1R介导的GABA能传播的降低促进了男性签名的灵活性 跟踪老鼠。首先，我将使用切片电生理学和rnascope来了解功能和 男性和雌性ST大鼠之间DMS内CB1R的基于表达的差异。第二，我会使用 化学遗传学和切片电生理学，以研究OFC-DMS投影对行为的贡献 灵活性和CB1R激活对该投影的影响。通过这些实验，我的目标是发现 关键的分子和基于电路的机制有助于柔韧性损害 与成瘾脆弱性。