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，可用于愉悦和精神刺激 性质，但具有引起不良精神并发症、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- 亚甲基二氧基吡咯丙酮(MDPV)是一种有效和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接触条件下使用。然而，合成卡西酮使用者经常使用 在连续几天内反复暴饮暴食地吸食药物，这还没有被建模 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，允许大鼠自我给予MDPV或生理盐水，连续96次 小时(4天)，然后在家中禁欲72小时(3天)。重复此过程以允许 总共5周的长时间药物自我给药与禁欲交替进行。下一步，动物 通过物体放置和识别任务对认知功能进行评估，然后进行分析 以寻找神经变性、神经炎症或氧化应激的潜在证据。动物自我-- 服用MDPV显示出高水平的药物摄入量(每96小时疗程100毫克/公斤)，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。 识别存储电路。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，无论它们是否延伸到认知灵活性的衡量标准，并调查潜在的 缓解这些影响的基本机制和方法。这些研究的首要假设是 在这个应用中提出的是MDPV引起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又相互关联的假设 目标。在具体目标1中，我们将考察性别和剂量对mdpv诱导的神经认知的影响。 功能障碍。在具体目标2中，我们将研究重复暴饮式MDPV摄入对认知的影响 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的机制。 (神经炎症或氧化应激)潜在的MDPV诱导的神经认知功能障碍。加在一起，这些 研究将有助于开发治疗干预措施，以抵消 合成卡替酮对认知和脑功能的影响。

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.