Chronic Stress and MDMA Neurotoxicity

描述（由申请人提供）： 这与压力和滥用安非他明和可卡因等药物的神经生物学有很大的重叠。3，4-亚甲二氧基甲基苯丙胺（MDMA）是一种苯丙胺衍生物，自1980年代以来，其滥用在全世界急剧增加。尽管MDMA对5-羟色胺（5-HT）末梢产生选择性神经毒性，但对MDMA使用的长期功能后果了解较少。此外，尚未对先前接触摇头丸与慢性压力之间的相互作用进行研究。我们的初步研究表明，5 HT，在腹侧被盖区（VTA）的水平，抑制MDMA诱导的多巴胺（DA）的释放在n。（NAcc）.因此，先前MDMA诱导的5 HT耗竭可能会抑制精神兴奋剂诱导的NAcc DA释放，破坏该系统的正常5 HT能调节，并增强滥用药物的应激相关DA能和奖励方面。还已知慢性应激显著影响海马体（HIPP）。由于5-HT抑制海马谷氨酸的传输，暴露于慢性应激后，MDMA诱导的5-HT终端的损害，可以增强的脆弱性的HIPP谷氨酸的兴奋性毒性作用。由此产生的HIPP兴奋性毒性可能是报告的在人类MDMA滥用者中观察到的记忆缺陷的基础。虽然MDMA诱导的对5-HT末端的损伤或单独的应激都不足以产生显著的后果，但它们可能协同作用，引起与增强的药物滥用和认知缺陷相关的显著的神经化学和功能变化。首要的假设是，MDMA诱导的神经毒性5 HT终端disinhibit DA释放的NAcc和谷氨酸释放的HIPP，其中每一个协同慢性应激，以提高药物奖励和产生兴奋性毒性的HIPP，分别。该假设将通过2个特定目的进行检验：（1）检查MDMA预处理大鼠随后暴露于轻度慢性不可预测应激方案的海马谷氨酸释放以及学习和记忆，（2）评估可卡因和MDMA自我给药期间MDMA对慢性应激诱导的DA释放变化的神经毒性作用。这些研究对先前MDMA暴露、慢性应激和随后药物自我给药的脆弱性之间可能的协同相互作用具有重要意义。

DESCRIPTION (provided by applicant): There is a significant overlap with the neurobiology of stress and abuse of drugs such as amphetamine and cocaine. 3,4-methylenedioxymethamphetamine (MDMA), is an amphetamine derivative whose abuse has dramatically increased worldwide since the 1980s. Although MDMA produces a selective neurotoxicity to serotonin (5HT) terminals, the long-term functional consequences of MDMA use are less understood. Moreover, the interactions between prior exposure to MDMA and chronic stress have not been examined. Our preliminary studies indicate that 5HT, at the level of the ventral tegmental area (VTA), dampens MDMA-induced dopamine (DA) release in n. accumbens (NAcc). Consequently, prior MDMA-induced 5HT depletions may disinhibit psychostimulant-induced NAcc DA release, disrupt the normal 5HTergic modulation of this system, and enhance the stress-associated DAergic and rewarding aspects of abused drugs. It also is known that chronic stress markedly affects the hippocampus (HIPP). Since 5HT inhibits hippocampal glutamate transmission, exposure to chronic stress after MDMA-induced damage to 5HT terminals could enhance the vulnerability of the HIPP to the excitotoxic effects of glutamate. The resultant excitotoxicity to the HIPP may underlie the reported memory deficits observed in human MDMA abusers. While neither MDMA-induced damage to 5HT terminals nor stress alone may be sufficient to produce marked consequences, they may' interact synergistically to cause dramatic neurochemical and functional changes associated with enhanced drug abuse and cognitive deficits. The overarching hypothesis is that MDMA-induced neurotoxicity to 5HT terminals disinhibits DA release in the NAcc and glutamate release in the HIPP, each of which synergizes with chronic stress to enhance drug reward and produce excitotoxicity to the HIPP, respectively. This hypothesis will be tested by 2 Specific aims: (1) examine hippocampal glutamate release as well as learning and memory in MDMA pre-treated rats subsequently exposed to a mild chronic unpredictable stress regimen and (2) assess the neurotoxic effects of MDMA on chronic stress-induced changes in DA release during cocaine and MDMA self-administration. These studies have significant implications for the possible synergistic interactions between prior MDMA exposure, chronic stress, and the vulnerability to subsequent drug self-administration.