Mechanisms of Amphetamine Action on Dopaminergic Signaling

描述（由申请人提供）：相当多的研究工作已被合理地用于确定安非他明的作用机制。然而，安非他明是否像最近对可卡因（另一种精神兴奋剂）所显示的那样，作用于相多巴胺能信号尚不清楚。考虑到多巴胺能神经传递模式在学习和动机行为中的作用，以及安非他明在治疗注意缺陷多动障碍及其高度成瘾性中的作用，预计会有一些参与。另一方面，虽然这两种药物都抑制多巴胺的吸收，但安非他明，而不是可卡因，会消耗多巴胺的囊泡储存。因此，安非他明可能不像可卡因那样具有增加伏隔核瞬时多巴胺浓度振幅的能力，这种能力可能是由相性或爆发性放电和胞外释放引起的。检查安非他明和相多巴胺能信号之间的联系是重要的，因为这种精神兴奋剂的行为相关机制尚未完全阐明。特别是，安非他明对行为的影响与透析多巴胺之间的分离表明，除了强直性多巴胺能信号传导外，还有其他目标。与在终末场产生多巴胺浓度瞬态的相性多巴胺能信号传导不同，强直性多巴胺能信号传导维持低水平、稳态或环境水平的脑细胞外多巴胺。为了解决与安非他明作用有关的这些重要问题，本项目将研究安非他明对相多巴胺能信号传导的影响。第一个目标是比较安非他命对老鼠和叙利亚仓鼠的刺激作用。虽然有单独的研究表明，叙利亚仓鼠对安非他命的敏感性低于包括大鼠在内的其他啮齿动物，但这种差异并没有在相同的条件下得到证实。通过在随后的实验中比较这两个物种的神经化学测量，安非他明对相多巴胺能信号的影响的行为相关性将被独特地评估。第二个目的是确定安非他明对伏隔核多巴胺摄取和胞外释放的影响，这一点尚未在体内建立。这些突触前机制调节多巴胺瞬态振幅。第三个目标将表征安非他明对伏隔核中多巴胺浓度瞬变的频率和幅度的影响，直接使用相同的方法，在自由运动的动物中使用快速扫描循环伏安法，该方法先前用于确定可卡因对相位多巴胺能信号的影响。这项研究将调查安非他明是如何影响大脑的，安非他明既是一种治疗药物，也是一种滥用药物。新的微传感器技术将应用于实验动物，以表征安非他明对与学习和动机有关的脑化学的影响。

DESCRIPTION (provided by applicant): Considerable research effort has justifiably been directed towards identifying the mechanisms of amphetamine action. However, whether amphetamine acts on phasic dopaminergic signaling, as has been shown recently for cocaine, another psychostimulant, is not known. Some involvement is anticipated, given the role proposed for this mode of dopaminergic neurotransmission in learning and motivated behavior and amphetamine's use in treating attention deficit hyperactivity disorder and its highly addictive nature. On the other hand, while both drugs inhibit dopamine uptake, amphetamine, but not cocaine, depletes vesicular stores of dopamine. Consequently, amphetamine may not share with cocaine the ability to increase the amplitude of dopamine concentration transients in the nucleus accumbens, presumably elicited by phasic or burst firing and exocytotic release. Examining the link between amphetamine and phasic dopaminergic signaling is significant, because the behaviorally relevant mechanisms by which this psychostimulant acts are not fully elucidated. In particular, documented dissociations between amphetamine's effects on behavior and dialysate dopamine suggest other targets besides tonic dopaminergic signaling. In contrast to phasic dopaminergic signaling, which generates dopamine concentration transients in terminal fields, tonic dopaminergic signaling maintains a low, steady-state or ambient level of brain extracellular dopamine. To address these important issues related to amphetamine action, the present project will investigate the effects of amphetamine on phasic dopaminergic signaling. The first aim will compare the stimulant effects of amphetamine in rats and Syrian hamsters. While separate studies suggest that Syrian hamsters are less sensitive to amphetamine than other rodents including rats, this difference has not been established under the same conditions. By comparing neurochemical measurements in these two species in the subsequent experiments, the behavioral relevance of amphetamine effects on phasic dopaminergic signaling will be uniquely assessed. The second aim will determine the effects of amphetamine on dopamine uptake and exocytotic dopamine release in the nucleus accumbens, which have not been established in vivo. These presynaptic mechanisms regulate dopamine transient amplitude. The third aim will characterize the effects of amphetamine on the frequency and amplitude of dopamine concentration transients in the nuclues accumbens directly using the same approach, fast-scan cyclic voltammetry in freely moving animals, that was previously used to establish cocaine effects on phasic dopaminergic signaling. This research will investigate how amphetamine, which is used both as a therapeutic agent and a drug of abuse, affects the brain. New microsensor technology will be employed in laboratory animals to characterize amphetamine's effect on brain chemistry related to learning and motivaton.