Opioid-induced changes to cannabinergic regulation of dopamine and motivation during protracted withdrawal

阿片类药物引起的大麻素能调节多巴胺和长期戒断期间动机的变化

• 批准号: 10319399
• 负责人: Devan Marc Gomez
• 金额: $ 3.12万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319399
• 关键词: Abstinence; Acute; Affect; Affective; Anatomy; Anhedonia; Anxiety; Attenuated; Behavior; Behavioral; CNR1 gene; Cannabinoids; Cell Nucleus; Cells; Characteristics; Consult; Data; Dependence; Detection; Development; Disinhibition; Dopamine; Dose; Drug usage; Electrophysiology (science); Epidemic; Etiology; Exhibits; Exposure to; Functional disorder; Goals; Hearing; Heterogeneity; Influentials; Intake; Intervention; Knowledge; Lateral; Learning; Link; Measures; Mediating; Mentors; Modeling; Morphine; Morphine Dependence; Motivation; Mus; Neurobiology; Neurotransmitters; Nucleus Accumbens; Opiate Addiction; Opioid; Output; Pathway interactions; Patients; Pharmaceutical Preparations; Physiology; Play; Positioning Attribute; Postdoctoral Fellow; Psychological reinforcement; Regulation; Relapse; Research; Rewards; Risk; Risk Factors; Role; Schedule; Scientist; Self Administration; Signal Transduction; Slice; Synapses; System; Technical Expertise; Testing; Therapeutic; Time; Ventral Tegmental Area; Withdrawal; Withdrawal Symptom; Work; acute symptom; addiction; base; behavioral study; cost; craving; dopaminergic neuron; drug craving; drug efficacy; drug relapse; effective intervention; efficacious treatment; endocannabinoid signaling; experimental study; gamma-Aminobutyric Acid; in vivo; mesolimbic system; motivated behavior; mouse model; negative affect; non-drug; novel; opioid abuse; opioid use; opioid use disorder; opioid withdrawal; optogenetics; preference; programs; research and development; reward processing; skills; symposium; symptom treatment; synaptic inhibition

PROJECT SUMMARY Opioid abuse remains a costly epidemic in the US, prompting research into new and effective interventions to curb addiction-like behavior. Amongst the therapeutic characteristics of opioids, their associated withdrawal effects are substantial and recognized to contribute to development of abuse and relapse. While acute somatic withdrawal symptoms are relatively well characterized, their prolonged affective counterparts are less understood. Regulating a broad array of affective behaviors, the mesolimbic dopamine (DA) system has been demonstrated as both necessary and sufficient for reward-related behavior towards opioids and withdrawal- related negative affect, with a canonical hypodopaminergic state following opioid dependence at least partially responsible for drug craving and relapse vulnerability. Despite this, limitations of previous studies concerning heterogeneity of mesolimbic circuitry and a shortage of assessments of opioid-induced long-term changes to motivated behavior and subsequent drug intake following dependence have stifled clear demonstrations of protracted motivational dysfunction and detection of underlying mechanism for the associated hypodopaminergic state. Growing evidence indicates that cannabinoid (CB) signaling is highly influential in regulating mesoaccumbal dopamine and opioid systems, including dopamine and opioid control of reinforcement, and that CB-based therapies may hold efficacy in treating negative affective states during acute/somatic withdrawal and perhaps opioid intake. Despite these promising data, data regarding how CB signaling is altered during opioid withdrawal and whether CB-therapies are efficacious in countering dependence-related changes in motivation for and intake of opioids with more protracted withdrawal are almost non-existent. This proposal builds off my research to date demonstrating that 1) morphine dependence promotes a long-lasting elevation in GABAA- mediated inhibitory tone specific to DA neurons in the lateral ventral tegmental area projecting to the lateral nucleus accumbens shell (latVTA-latShell), 2) prior dependence increases motivation for and intake of morphine, and 3) elevations in GABA signaling align with an apparent tolerance to CB1-induced disinhibition of lateral VTA DA firing. In Aim2/Exp1, I will utilize ex vivo slice electrophysiology to assess alterations in synaptic strength and CB-dependent regulation of GABAergic afferents from the rostromedial tegmental nucleus (RMTg) to latVTA- latShell DA cells. Behavior studies in Aim2/Exp2 will extend upon data demonstrating increased effort-based motivated responding for morphine under protracted withdrawal conditions by measuring cannabinoid-induced alteration of this effect. Completing these experiments will support my research development by adding technical skills in more sophisticated electrophysiology and behavioral approaches. Further, results will fill critical unknowns regarding mechanisms underlying ostensibly important changes in DA function and behavior that drive OUD and characterize the longer-lasting benefits and limitations of CB-based interventions.

项目摘要 阿片类药物滥用在美国仍然是一种代价高昂的流行病，促使人们研究新的有效干预措施， 遏制成瘾行为。在阿片类药物的治疗特征中， 影响是巨大的，并被认为有助于滥用和复发的发展。虽然急性躯体 戒断症状的特征相对较好，其长期的情感对应物较少 明白中脑边缘多巴胺（DA）系统调节着广泛的情感行为， 证明对阿片类药物和戒断的奖励相关行为是必要和充分的- 相关的负面影响，在阿片类药物依赖后至少部分出现典型的多巴胺能减退状态 导致了对毒品的渴望和复发的脆弱性尽管如此，以前的研究局限于 中脑边缘回路的异质性和缺乏对阿片类药物诱导的长期变化的评估， 有动机的行为和随后的药物摄入后的依赖性已经扼杀了明确的证据， 长期的动机功能障碍和相关的低多巴胺能的潜在机制的检测 状态越来越多的证据表明，大麻素（CB）信号在调节 伏隔核多巴胺和阿片系统，包括多巴胺和阿片类药物对强化的控制，并且 基于CB的疗法可以有效治疗急性/躯体戒断期间的负性情感状态， 可能是阿片类药物摄入。尽管有这些有希望的数据，关于CB信号传导在阿片类药物作用期间如何改变的数据， 戒断以及CB疗法是否能有效对抗依赖相关的动机变化 服用阿片类药物并更长时间停药的情况几乎不存在。这个提议建立在我的 迄今为止的研究表明，1）吗啡依赖促进GABAA的长期升高， 介导的抑制性音调特异性的DA神经元在外侧腹侧被盖区投射到外侧 神经核壳（latVTA-latShell），2）先前依赖性增加吗啡的动机和摄入， 和3）GABA信号的升高与CB 1诱导的外侧VTA去抑制的明显耐受性一致 地方检察官开火了在目标2/实验1中，我将利用离体切片电生理学来评估突触强度的变化， 中脑背盖吻内侧核（RMTg）向latVTA的GABA能传入的CB依赖性调节 latShell DA细胞。Aim 2/Exp 2中的行为研究将根据数据扩展，以证明基于努力的行为增加。 通过测量大麻素诱导的吗啡长期戒断条件下的动机反应 改变这种效果。完成这些实验将支持我的研究发展， 更复杂的电生理学和行为学方法的技能。此外，结果将填补关键 关于DA功能和行为表面上重要变化的潜在机制的未知数， 推动OUD，并描述基于CB的干预措施的长期益处和局限性。