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

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 自我注射盐水的动物在物体识别方面表现出表现缺陷，但在物体放置方面表现不佳。 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，无论它们是否延伸到认知灵活性的措施，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。

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.