Mechanisms of Amphetamine Action on Dopaminergic Signaling

描述（由申请人提供）：相当多的研究工作显然是针对确定安非他明的作用机制。然而，安非他明是否作用于相位多巴胺能信号，如最近已显示的可卡因，另一种精神兴奋剂，是未知的。一些参与是预期的，考虑到这种模式的多巴胺能神经传递在学习和动机行为中的作用，以及安非他明在治疗注意力缺陷多动障碍及其高度成瘾性中的用途。另一方面，虽然这两种药物都抑制多巴胺的摄取，但安非他明，而不是可卡因，耗尽了多巴胺的囊泡储存。因此，安非他明可能不会与可卡因分享的能力，以增加多巴胺浓度瞬变的幅度在丘脑核，推测引起的相位或突发发射和胞吐释放。检查安非他明和相性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，记录的安非他明对行为和透析液多巴胺的影响之间的分离表明，除了紧张性多巴胺能信号传导的其他目标。与在终末场中产生多巴胺浓度瞬变的阶段性多巴胺能信号传导相反，强直性多巴胺能信号传导维持脑细胞外多巴胺的低、稳态或环境水平。为了解决这些重要的问题，安非他明的行动，本项目将调查安非他明对相多巴胺能信号的影响。第一个目标是比较安非他明对大鼠和叙利亚仓鼠的刺激作用。虽然单独的研究表明，叙利亚仓鼠对安非他明的敏感性低于其他啮齿动物，包括大鼠，但在相同条件下，这种差异尚未确定。通过比较在这两个物种在随后的实验中的神经化学测量，安非他明对相多巴胺能信号传导的影响的行为相关性将被独特地评估。第二个目标将确定安非他明对多巴胺摄取和胞吐多巴胺释放的影响，这在体内还没有建立。这些突触前机制调节多巴胺瞬时振幅。第三个目标将直接使用相同的方法，快速扫描循环伏安法在自由移动的动物，这是以前用于建立可卡因对相多巴胺能信号的影响，表征安非他明对多巴胺浓度瞬变的频率和幅度的影响。这项研究将调查安非他明是如何影响大脑的，安非他明既被用作治疗剂，也被用作滥用药物。新的微传感器技术将被用于实验室动物，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.