Characterization and reversal of neurocognitive dysfunction produced by long-term synthetic cathinone use

长期使用合成卡西酮引起的神经认知功能障碍的特征和逆转

基本信息

批准号：
9978792
负责人：
M. FOSTER OLIVE
金额：
$ 37.96万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978792
关键词：
Abstinence Address Alcohol or Other Drugs use Alkaloids Amphetamines Animals Antioxidants Brain Brain region Catha edulis Cocaine Cognition Cognitive Dependence Development Dose Drug Costs Exhibits Female Functional disorder Goals Histologic Home environment Hour Impaired cognition Impairment Individual Intake Ketoprofen Lead Legal Long-Term Effects Measures Mediating Medical Methamphetamine Modeling Nerve Degeneration Neurocognitive Neurocognitive Deficit Non-Steroidal Anti-Inflammatory Agents Oxidative Stress Pattern Performance Pharmaceutical Preparations Pharmacologic Actions Pharmacology Procedures Property Public Health Rattus Resistance Reversal Learning Risk Rodent Rodent Model Saline Self Administration Societies Testing Therapeutic Intervention Time bath salts brain tissue cognitive function cognitive testing flexibility high risk histopathological examination improved inhibitor/antagonist khat male memory recognition monoamine mortality neural circuit neuroinflammation neuropsychiatry neurotoxicity novel object recognition psychostimulant public health relevance reuptake sex socioeconomics synthetic drug systemic toxicity tempol therapeutic development

项目摘要

ABSTRACT Synthetic cathinones are novel psychoactive substances used for their euphorigenic and psychostimulant properties, but carry a significant risk of inducing adverse psychiatric complications, systemic toxicity, and patterns of abuse and dependence. We recently demonstrated that the synthetic cathinone 3,4- methylenedioxypyrovalerone (MDPV), a potent and long-lasting monoamine reuptake inhibitor, is readily self- administered by rodents under limited access conditions. However, synthetic cathinone users frequently engage in repeated binge-like patterns of drug intake across several consecutive days, which have not yet been modeled in rodents to determine potential detrimental effects on cognition and brain function. To address this, we recently conducted preliminary studies in which rats were allowed to self-administer MDPV or saline for 96 consecutive hrs (4 days), followed by 72 hrs (3 days) of abstinence in the home cage. This procedure was repeated to allow for a total of 5 weeks of prolonged drug self-administration alternating with periods of abstinence. Next, animals underwent assessment of cognitive function using object placement and recognition tasks, followed by analysis of brain tissue for potential evidence of neurodegeneration, neuroinflammation, or oxidative stress. Animals self- administering MDPV displayed high levels of drug intake (>100 mg/kg per 96-hr session), and compared to animals self-administering saline, showed performance deficits in object recognition but not object placement. We also observed evidence of MDPV-induced neurodegeneration, neuroinflammation, and oxidative stress in the recognition memory circuit. However, additional studies are needed to further examine the dose and sex- dependency of these effects, whether they extend to measures of cognitive flexibility, and to investigate potential underlying mechanisms and approaches for mitigating these effects. The overarching hypothesis of the studies proposed in this application is that MDPV-induced neurocognitive dysfunction is highly influenced by sex, dose, and neuroinflammatory mechanisms. To test this hypothesis, we propose three independent yet inter-related aims. In Specific Aim 1, we will examine the influence of sex and dose on MDPV-induced neurocognitive dysfunction. In Specific Aim 2, we will examine the effects of repeated binge-like MDPV intake on cognitive flexibility. Finally, in Specific Aim 3, we will pharmacologically investigate potential mechanisms (neuroinflammation or oxidative stress) underlying MDPV-induced neurocognitive dysfunction. Together, these studies will assist in the development of therapeutic interventions to counteract the detrimental effects of synthetic cathinones on cognition and brain function.

抽象的综合cathinones是新颖的精神活性物质，用于其欣快和精神刺激剂财产，但具有引起不良精神病并发症，全身毒性和虐待和依赖的模式。我们最近证明了合成的Cathinone 3,4-- 甲基二氧甲状甲甲酮（MDPV）是一种有效且持久的单胺再摄取抑制剂，很容易自我自我在有限的进入条件下由啮齿动物管理。但是，合成Cathinone使用者经常参与在连续几天的重复暴饮暴食模式中，尚未对此进行建模在啮齿动物中，以确定对认知和大脑功能的潜在有害影响。为了解决这个问题，我们最近进行了初步研究，其中允许大鼠连续96次自我管理MDPV或盐水 HRS（4天），其次是家庭笼中的72小时（3天）。重复此过程以允许总计5周的长时间药物自我给药，与禁欲期交替。接下来，动物使用对象放置和识别任务对认知功能进行评估，然后进行分析脑组织的神经退行性，神经炎症或氧化应激的潜在证据。动物自我管理MDPV显示出高水平的药物摄入量（每96小时疗程> 100 mg/kg），并与动物自我管理盐水，在物体识别中表现出性能缺陷，但不能放置对象。我们还观察了MDPV诱导的神经退行性，神经炎症和氧化应激的证据。识别记忆电路。但是，需要进一步研究剂量和性别 - 这些影响的依赖性，它们是否扩展到认知灵活性的度量并研究潜力减轻这些影响的基本机制和方法。研究的总体假设在此应用中提出的是MDPV诱导的神经认知功能障碍受性别，剂量，和神经炎症机制。为了检验这一假设，我们提出了三个独立但相互关联的目标。在特定目标1中，我们将研究性别和剂量对MDPV诱导的神经认知的影响功能障碍。在特定目标2中，我们将研究重复的暴饮暴食MDPV摄入量对认知的影响灵活性。最后，在特定目标3中，我们将在药理上研究潜在的机制（神经炎症或氧化应激）基础MDPV诱导的神经认知功能障碍。在一起，这些研究将有助于制定治疗干预措施，以抵消关于认知和大脑功能的合成阴茎。