Imaging In Vivo Neural Mechanisms of Synthetic Cathinones (Bath Salts)

合成卡西酮（浴盐）的体内神经机制成像

• 批准号: 8892408
• 负责人: MARCELO FEBO
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8892408
• 关键词: Acute; Affect; Affective; Aggressive behavior; Amygdaloid structure; Anxiety; Area; Bathing; Behavior; Behavioral; Bipolar Disorder; Brain; Brain region; Case Study; Chemicals; Chronic; Clinical; Cocaine; Cognitive; Consumption; Data; Delirium; Dose; Drug Formulations; Emotions; Euphoria; Feeling suicidal; Female; Functional Magnetic Resonance Imaging; Future; Hallucinations; Hallucinogens; Hour; Image; Impaired cognition; In Vitro; Individual; Insula of Reil; Intake; Intoxication; Investigation; Knowledge; Lead; Legal; Major Depressive Disorder; Mediating; Mental Depression; Mental Health; Methamphetamine; Neuraxis; Neurobiology; Nucleus Accumbens; Outcome; Panic Attack; Pharmaceutical Preparations; Prefrontal Cortex; Public Health; Rattus; Recording of previous events; Reporting; Research; Rest; Rewards; Salts; Schizophrenia; Series; Signal Transduction; Site; Sodium Chloride; Street Drugs; Structure; Suicide; Symptoms; System; Testing; Time; Toxic effect; Ventral Tegmental Area; Violence; Work; anxiety-like behavior; base; behavioral response; blood oxygen level dependent; cathinone; cognitive function; craving; dopamine transporter; experience; in vivo; male; monoamine; neurochemistry; neuromechanism; novel; pre-clinical; psychostimulant; public health relevance; pyrovalerone; relating to nervous system; research study; response; social; stem

 DESCRIPTION (provided by applicant): Street drugs known as `bath salts' represent an emergent danger to public health. Chemicals present in formulations of bath salts elicit neurochemical actions and behavioral responses that resemble the combined effects of other illegal stimulants, hallucinogens and empathogenic agents. Hours after the euphorigenic effects of bath salts wane, there is an onset of a `crash' that in many cases include a strong negative affective state with excited delirium, major depression and violent aggressive behavior. These effects last hours, days and even weeks after ceasing intake. There is still a knowledge gap with regards to the sites of action within the brain that may cause these effects. There is also a need for preclinical data to help understand the onset of aggressive behavior and negative affective states that may lead to violence and suicide, even in individuals with no prior history of psychiatric illness. To begin to investigate the neural actions of bath salt drugs we carried out a preliminary experiment to examine blood oxygen level dependent (BOLD) signal changes in rats treated with various doses of 3,4-methylenedioxypyrovalerone (MDPV), one of the most harmful agents present in bath salts. Consistent with previous reports by other pioneering groups, MDPV elicited a robust activation of the reward system, including nucleus accumbens and ventral tegmental area, and areas of the prefrontal cortex such as insular and orbital cortices. Elevated doses of MDPV also caused a dramatic global reduction in resting state functional connectivity (rsFC) at 1 hour after administration. However, at the very highest dose tested a selective increase in rsFC emerged between the amygdala and regions of the prefrontal cortex. Our central hypothesis is that following bath salt exposure there is a progressive, time-dependent increase in anxiety and aggressive behavior with diminished cognitive function that is characterized centrally by a dramatic reduction in the brain's intrinsic functional connectivity. T test this hypothesis, in aim 1 we will determine the temporal progression of social, affective and cognitive behaviors following MDPV administration. In aim 2 we will determine MDPV-evoked BOLD signal changes and alterations in rsFC. The overall reduction in synchronous brain BOLD activity along with greater BOLD synchrony between prefrontal areas and amygdala might be associated with the negative affective states elicited by binge consumption, especially at higher doses. This might represent an important signature of MDPV's mechanism of action to be exploredin the present proposal. From a public health perspective, the present series of experiments will provide the urgently needed data that will help develop strategies to treat acute bath salts intoxication. This will be possible with a better understanding of the temporal progression of the negative behavioral effects and the sites of actions of these agents within the central nervous system.

 描述（由申请人提供）：被称为“浴盐”的街头毒品对公众健康构成紧急危险。浴盐配方中存在的化学物质会引起神经化学作用和行为反应，类似于其他非法兴奋剂、致幻剂和致病剂的综合作用。在浴盐的欣快作用减弱后几个小时，就会出现一种“崩溃”，在许多情况下，这种崩溃包括一种强烈的负面情绪状态，包括兴奋性谵妄、重度抑郁和暴力攻击行为。这些影响在停止摄入后持续数小时，数天甚至数周。关于大脑中可能导致这些影响的作用部位，仍然存在知识差距。还需要临床前数据来帮助理解可能导致暴力和自杀的攻击性行为和消极情感状态的发作，即使在没有精神病史的个体中也是如此。为了开始研究浴盐药物的神经作用，我们进行了一项 在用各种剂量的3，4-亚甲二氧基吡咯戊酮（MDPV）处理的大鼠中，检测血氧水平依赖性（BOLD）信号变化的初步实验，MDPV是浴盐中存在的最有害的试剂之一。与其他先驱小组先前的报告一致，MDPV引起了奖励系统的强烈激活，包括延髓核和腹侧被盖区，以及前额叶皮层的区域，如岛叶和眶皮层。MDPV剂量升高还导致给药后1小时静息状态功能连接（rsFC）显著降低。然而，在测试的最高剂量下，杏仁核和前额皮质区域之间出现了rsFC的选择性增加。我们的中心假设是，在浴盐暴露后，焦虑和攻击性行为会随着时间的推移而逐渐增加，认知功能减弱，其主要特征是大脑内在功能连接的急剧减少。T检验这一假设，在目标1中，我们将确定MDPV给药后社交、情感和认知行为的时间进展。在目标2中，我们将确定MDPV诱发的BOLD信号变化和rsFC的改变。大脑同步BOLD活动的总体减少沿着前额区和杏仁核之间的BOLD同步性增强，可能与暴饮暴食引起的负面情感状态有关，尤其是在较高剂量下。这可能是MDPV作用机制的一个重要标志，将在本提案中加以探讨。从公共卫生的角度来看，目前的一系列实验将提供迫切需要的数据，这将有助于制定治疗急性浴盐中毒的策略。这将是可能的，更好地了解的时间进展的负面行为的影响和网站的行动，这些代理人在中枢神经系统。