The mechanism and sex-specific effects of nicotinamide on cue-primed cocaine seeking

烟酰胺对线索引发的可卡因寻求的机制和性别特异性影响

• 批准号: 10248338
• 负责人: Emily Anne Witt
• 金额: $ 2.95万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-05-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10248338
• 关键词: Abstinence; Affect; Amygdaloid structure; Animal Model; Astrocytes; Attenuated; Automobile Driving; Behavior; Behavioral; Behavioral Mechanisms; Brain; Cell Nucleus; Chronic; Cocaine; Cocaine Abuse; Cocaine Dependence; Coenzymes; Confocal Microscopy; Cues; Data; Dependence; Development; Disease; Dopamine; Dose; Drug Exposure; Drug abuse; Drug usage; Extinction (Psychology); FDA approved; Female; Financial Hardship; Fluorescence Microscopy; Goals; Health; Human; Immunohistochemistry; Impairment; Injections; Intervention; Link; Measurement; Measures; Mediating; Microscopy; Modeling; Motivation; NADP; Nature; Neurons; Niacinamide; Nucleus Accumbens; Nutrient; Oxidative Stress; Oxidative Stress Induction; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Poly(ADP-ribose) Polymerases; Production; Publications; Rattus; Reactive Inhibition; Reactive Oxygen Species; Relapse; Reporting; Research; Role; Science; Self Administration; Sex Differences; Testing; Training; addiction; burden of illness; cocaine exposure; cocaine overdose; cocaine self-administration; cocaine use; conditioned place preference; confocal imaging; design; drug seeking behavior; effective intervention; effective therapy; experimental study; inhibitor/antagonist; interest; male; novel; overdose death; pre-clinical; preference; psychostimulant; response; reward circuitry; sex; specific biomarkers

Project Summary No FDA approved pharmacological treatments exist for psychostimulant use disorders. Accordingly, development of effective interventions that can countermand the cellular adaptations which drive relapse to drug use remains a priority. Existing evidence indicates that cocaine use leads to elevated markers of oxidative stress, in both humans and preclinical animal models of addiction, and importantly that these markers may contribute to drug seeking behaviors. Nicotinamide (NAM), a form of vitamin B3, component of crucial coenzymes NAD+ and NADP, and poly(ADP-ribose)polymerase (PARP-1) inhibitor can inhibit or reverse markers of oxidative stress. Preliminary data for this application indicate that systemic administration of NAM following cocaine self-administration can specifically reduce reinstatement to cue-primed seeking in male, but not female, rats. The overall goal of this application is to test hypotheses regarding the mechanism behind NAM’s ability to reduce cue-reinstatement in males. Aim 1 will test the hypothesis that NAM’s ability to inhibit PARP-1 contributes to the observed behavioral effect. This will be accomplished with direct delivery of a PARP-1 inhibitor to the central nucleus of the amygdala (CeA) followed by reinstatement testing (Aim 1a) as well as measurement of PARP-1 activity following cocaine self-administration and chronic NAM administration (Aim 1b). The CeA is of particular interest, as direct inhibition of PARP-1 in the CeA has been previously shown to reduce conditioned place preference to cocaine, and the CeA has been implicated specifically in cue- primed reinstatement. Aim 2 will test the hypothesis that NAM reverses cocaine-induced increases in a specific biomarker for oxidative stress in the nucleus accumbens (NAc) and CeA. This will be accomplished through immunohistochemistry and confocal imaging of a cellular marker for oxidative stress following self- administration and extinction. Interestingly, sex differences in the effects of PARP-1 inhibition and NAM treatment have been previously reported, but not in a drug exposure paradigm. Likewise, sex differences in oxidative stress are well known, but have not been examined in drug abuse models. Therefore, the experiments outlined in this proposal will not only inform the utility of NAM as a candidate intervention for responsiveness to drug-paired cues, but will also advance our understanding of the basic cellular responses to cocaine in the brain. I hypothesize that direct inhibition of PARP-1 in the CeA will reduce cue-primed reinstatement, but not cocaine-primed reinstatement, and that NAM administration will reduce cocaine-induced elevated PARP-1 activity in male rats (Aim 1). Further, I hypothesize that NAM administration will reduce cocaine-dependent oxidative stress in the brains of male, but not female rats (Aim 2). Collectively, this proposal will (1) provide training in quantitative fluorescent microscopy, (2) will provide information regarding induction of oxidative stress by cocaine in male and female rats, and (3) will more clearly elucidate the mechanism by which NAM impairs reinstatement of cocaine seeking.

项目摘要 没有FDA批准的药物治疗精神兴奋剂使用障碍。因此，委员会认为， 开发有效的干预措施，可以消除促使复发的细胞适应， 吸毒仍然是一个优先事项。现有证据表明，可卡因的使用导致氧化应激标志物的升高， 应激，在人类和成瘾的临床前动物模型中，重要的是，这些标志物可以 有助于寻求毒品的行为。烟酰胺（NAM），维生素B3的一种形式， 辅酶NAD+和NADP，以及聚（ADP-核糖）聚合酶（PARP-1）抑制剂可以抑制或逆转 氧化应激的标志物。该应用的初步数据表明，NAM的全身给药 可卡因自我给药后可以特异性地减少男性线索启动寻求的复动， 不是母的是老鼠这个应用程序的总体目标是测试关于背后机制的假设 NAM减少男性线索恢复的能力。目标1将检验NAM抑制 PARP-1有助于观察到的行为效应。这将通过直接提供一个 PARP-1抑制剂对杏仁核中央核（CeA）的作用，随后进行恢复试验（Aim 1a）， 以及可卡因自我给药和长期NAM给药后PARP-1活性的测量 (Aim 1 b）。CeA是特别感兴趣的，因为在CeA中PARP-1的直接抑制先前已经被发现。 显示减少可卡因的条件性位置偏好，CeA特别涉及线索- 准备复职目的2将检验NAM逆转可卡因诱导的特异性神经递质增加的假设。 本发明涉及一种用于神经核（NAc）和CeA中的氧化应激的生物标志物。这将通过以下方式实现： 免疫组织化学和共聚焦成像技术检测自体免疫后氧化应激细胞标志物 管理和灭绝。有趣的是，PARP-1抑制和NAM作用的性别差异 以前曾报道过治疗，但没有在药物暴露范例中。同样， 氧化应激是众所周知的，但尚未在药物滥用模型中进行研究。因此 该提案中概述的实验不仅将告知NAM作为候选干预措施的效用， 对药物配对线索的反应，但也将促进我们对基本细胞反应的理解， 大脑中的可卡因我假设直接抑制CeA中的PARP-1会减少线索启动， 恢复，但不是可卡因引发的恢复，不结盟运动的管理将减少可卡因引起的 雄性大鼠PARP-1活性升高（目的1）。此外，我假设不结盟运动政府将减少 可卡因依赖性氧化应激在雄性大鼠的大脑中，而不是雌性大鼠（目的2）。总的来说，这 建议书将（1）提供定量荧光显微镜培训，（2）提供以下信息 可卡因在雄性和雌性大鼠中诱导氧化应激，以及（3）将更清楚地阐明 不结盟运动削弱可卡因寻求恢复的机制。