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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：
10225324
负责人：
M. FOSTER OLIVE
金额：
$ 37.86万
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 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10225324
关键词：
Abstinence Address Alkaloids Amphetamines Animals Antioxidants Brain Brain region Catha edulis Cocaine Cognition Cognitive Dependence Development Dose Drug Costs Exhibits Female Functional disorder Goals Histologic Home 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 substance use 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.

摘要合成卡西酮是一种新型的精神活性物质，具有欣快性和精神兴奋性性质，但具有诱导不良精神并发症、全身毒性和滥用和依赖的模式。我们最近证明，合成卡西酮3，4- 亚甲二氧基吡咯戊酮（MDPV）是一种有效的长效单胺再摄取抑制剂，由啮齿动物在有限的访问条件下管理。然而，合成卡西酮使用者经常参与在连续几天重复的暴食式药物摄入模式中，以确定对认知和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，其中大鼠连续96次自我给予MDPV或生理盐水小时（4天），然后在饲养笼中禁欲72小时（3天）。重复该过程以允许持续总共5周的延长的药物自我给药，与禁欲期交替。接下来，动物使用物体放置和识别任务进行认知功能评估，然后分析脑组织的神经变性，神经炎症，或氧化应激的潜在证据。动物自我- 给予MDPV显示出高水平的药物摄入（>100 mg/kg/96小时疗程），并且与动物自我施用盐水，显示出在物体识别方面的表现缺陷，但不是物体放置。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，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，它们是否延伸到认知灵活性的测量，并调查潜在的减轻这些影响的基本机制和办法。研究的首要假设是在该申请中提出MDPV诱导的神经认知功能障碍受性别，剂量，和神经炎症机制。为了验证这一假设，我们提出了三个独立但相互关联的目标。在具体目标1中，我们将检查性别和剂量对MDPV诱导的神经认知功能的影响。功能障碍在具体目标2中，我们将研究重复暴食式MDPV摄入对认知功能的影响。灵活性.最后，在具体目标3中，我们将进一步研究潜在的机制（神经炎症或氧化应激）是MDPV诱导的神经认知功能障碍的基础。所有这些研究将有助于开发治疗干预措施，以抵消合成卡西酮对认知和大脑功能的影响。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Nuclear factor kappa B signaling within the rat nucleus accumbens core sex-dependently regulates cue-induced cocaine seeking and matrix metalloproteinase-9 expression.

DOI：
10.1016/j.bbi.2022.03.002
发表时间：
2022-05
期刊：
Brain, behavior, and immunity
影响因子：
0
作者：
通讯作者：

Effects of heroin on rat prosocial behavior.

海洛因对大鼠亲社会行为的影响。

DOI：
10.1111/adb.12633
发表时间：
2019
期刊：
Addiction biology
影响因子：
3.4
作者：
Tomek,SevenE;Stegmann,GabrielaM;Olive,MFoster
通讯作者：
Olive,MFoster

Neuroimmune Mechanisms as Novel Treatment Targets for Substance Use Disorders and Associated Comorbidities.

DOI：
10.3389/fnins.2021.650785
发表时间：
2021
期刊：
Frontiers in neuroscience
影响因子：
4.3
作者：
Namba MD;Leyrer-Jackson JM;Nagy EK;Olive MF;Neisewander JL
通讯作者：
Neisewander JL

Restoration of prosocial behavior in rats after heroin self-administration via chemogenetic activation of the anterior insular cortex.

通过前岛叶皮质的化学遗传学激活，海洛因自我给药后大鼠的亲社会行为恢复。

DOI：
10.1080/17470919.2020.1746394
发表时间：
2020
期刊：
Social neuroscience
影响因子：
2
作者：
Tomek,SevenE;Stegmann,GabrielaM;Leyrer-Jackson,JonnaM;Piña,Jose;Olive,MFoster
通讯作者：
Olive,MFoster

Effects of repeated binge intake of the pyrovalerone cathinone derivative 3,4-methylenedioxypyrovalerone on prefrontal cytokine levels in rats - a preliminary study.