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：
9458065
负责人：
M. FOSTER OLIVE
金额：
$ 38万
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/9458065
关键词：
Abstinence Address Alcohol or Other Drugs use Alkaloids Amphetamines Animals Antioxidants Brain Brain region Catha edulis Cocaine Cognition Cognitive Dependence Dependency 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 Self-Administered Societies Testing Time brain tissue cathinone 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 therapy 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.

抽象的合成卡西酮是新型精神活性物质，用于产生欣快感和精神兴奋剂特性，但具有诱发不良精神并发症、全身毒性和虐待和依赖的模式。我们最近证明了合成卡西酮 3,4- 亚甲二氧基吡咯戊酮 (MDPV) 是一种有效且持久的单胺再摄取抑制剂，很容易自我由啮齿动物在有限的进入条件下进行管理。然而，合成卡西酮使用者经常参与连续几天重复的类似暴饮暴食的药物摄入模式，尚未建模在啮齿动物中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 次自我施用 MDPV 或盐水小时（4 天），然后在家里的笼子里禁欲 72 小时（3 天）。重复此过程以允许总共 5 周的长期自我给药与禁欲期交替。接下来是动物使用物体放置和识别任务评估认知功能，然后进行分析脑组织的潜在神经退行性变、神经炎症或氧化应激的证据。动物自施用 MDPV 显示出高水平的药物摄入量（每 96 小时>100 mg/kg），并且与自我注射生理盐水的动物在物体识别方面表现出缺陷，但在物体放置方面却没有表现出缺陷。我们还观察到 MDPV 诱导的神经变性、神经炎症和氧化应激的证据识别记忆电路。然而，还需要更多的研究来进一步检查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测量，并调查潜在的减轻这些影响的根本机制和方法。研究的总体假设该申请中提出的是，MDPV 引起的神经认知功能障碍很大程度上受性别、剂量、和神经炎症机制。为了检验这个假设，我们提出了三个独立但相互关联的目标。在具体目标 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。在具体目标 2 中，我们将研究反复暴饮暴食 MDPV 对认知的影响灵活性。最后，在具体目标 3 中，我们将从药理学角度研究潜在机制（神经炎症或氧化应激）潜在的 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，以抵消不良影响合成卡西酮对认知和大脑功能的影响。