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重叠。3，4-亚甲基二氧基甲基苯丙胺(MDMA)是一种苯丙胺衍生物，自1980年代以来在全球范围内滥用急剧增加。尽管MDMA对5-羟色胺(5-羟色胺)终末产生选择性神经毒性，但对使用MDMA的长期功能后果了解较少。此外，先前接触MDMA和慢性压力之间的交互作用还没有被研究过。我们的初步研究表明，在腹侧被盖区(VTA)水平，5-羟色胺(5-HT)可抑制MDMA诱导的伏隔核(NAcc)多巴胺(DA)的释放。因此，先前MDMA诱导的5-羟色胺的耗竭可能会抑制精神刺激剂诱导的NAcc DA的释放，扰乱该系统的正常5H能调制，并增强滥用药物的应激相关DAR能和奖赏方面。众所周知，慢性应激显著影响海马区(HIPP)。由于5-羟色胺抑制了海马谷氨酸的传递，在MDMA损伤5-羟色胺终末后暴露于慢性应激可增强HIPP对谷氨酸的兴奋性毒性效应的易感性。由此产生的对HIPP的兴奋毒性可能是已报道的人类MDMA滥用者记忆缺陷的基础。虽然MDMA对5HT终末的损伤或压力本身都不足以产生显著的后果，但它们可能会协同作用，导致与药物滥用和认知缺陷增加相关的显著神经化学和功能变化。最主要的假设是，MDMA对5HT终末的神经毒性抑制了NAcc中DA的释放和Hipp中谷氨酸的释放，两者分别与慢性应激协同作用，增强了药物奖赏，并对Hipp产生兴奋毒性。这一假说将通过两个特定的目标来检验：(1)检测MDMA预处理大鼠的海马谷氨酸释放以及学习和记忆，随后暴露于轻度的慢性不可预测的应激方案，以及(2)评估MDMA在可卡因和MDMA自身给药期间对慢性应激诱导的DA释放变化的神经毒性作用。这些研究对于先前的MDMA暴露、慢性应激和随后的药物自我给药易感性之间可能的协同作用具有重要的意义。

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.