AMPHETAMINE, INSULIN AND THE DA TRANSPORTER IN VIVO

安非他明、胰岛素和体内 DA 转运蛋白

• 批准号: 6856893
• 负责人: LYNETTE C DAWS
• 金额: $ 14.6万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6856893
• 关键词: amphetamines; behavioral habituation /sensitization; body physical activity; clearance rate; corpus striatum; diabetes mellitus; dopamine transporter; hormone regulation /control mechanism; hyperinsulinism; insulin; insulin receptor; laboratory rat; neurotransmitter transport; nucleus accumbens; pharmacokinetics; phosphatidylinositol 3 kinase

DESCRIPTION (provided by applicant): Drug abuse is a prevalent psychiatric disorder with immense negative public health consequences. As a result, understanding its neural underpinnings is a focus of intense research. The dopamine (DA) transporter (DAT) is a primary site of action of drugs of abuse such as amphetamine and is critical in regulating DA neurotransmission by high affinity transport of DA into the terminal. Understanding how the DAT is regulated is therefore of fundamental importance to studies of amphetamine abuse. In this regard, there is converging evidence that insulin can produce profound regulatory control of DAT activity. It is known for example that both food restriction as well as experimentally-induced diabetes have major effects on behavioral responses to amphetamine. The significance of these observations is underlined by the high co-morbidity of eating disorders and drug abuse. Recently it has been reported that rates of DA uptake are decreased in hypoinsulinemic rats and that insulin applied intracerebroventricularly to rats or to cells stably transfected with the DAT increases DA uptake. Importantly, it seems that insulin can interfere with the action of amphetamine at the DAT and can prevent amphetamine-induced internalization of the DAT. Of particular importance to the present proposal is that diabetic rats with a history of amphetamine self-administration show increased rather than decreased DA uptake. Insulin and its signaling pathways may therefore represent a novel target for the development of new treatments for drug abuse. To date no studies have assessed the role of insulin in controlling DAT activity in vivo. Because of the potential impact of insulin in promoting the abuse potential of drugs the proposed study will use an innovative approach, high-speed chronoamperometry, to measure insulin-dependent changes in DA efflux and clearance in vivo. Because a major signaling mechanism that underlies insulin's cellular actions is stimulation of phosphatidylinositol (PI)-3 kinase these studies will also test the hypothesis that DA effiux and clearance will be increased and decreased respectively, upon activation and inhibition of PI-3 kinase. Importantly, these studies will determine the relationship between the action of amphetamine and insulin status as they relate to DAT activity. Our general hypothesis is that the kinetics of DA efflux and clearance as well the locomotor stimulatory effects of amphetamine will be tightly correlated with insulin status. Restoration of insulin to normal levels will restore normal responses. The results obtained here will not only improve our fundamental understanding of DAT regulation but importantly the neural circuitry controlling reward and motivation, as well as provide a framework for a larger RO1 application. In turn, these studies may help to illuminate the neural mechanisms underlying the high co-morbidity of eating disorders and drug abuse.

描述（由申请人提供）：药物滥用是一种普遍的精神疾病，具有巨大的负面公共卫生后果。结果，了解其神经基础是激烈研究的重点。多巴胺（DA）转运蛋白（DAT）是诸如苯丙胺等滥用药物的主要作用部位，对于通过DA向末端的高亲和力运输来调节DA神经传递至关重要。因此，了解如何调节DAT对于苯丙胺滥用研究至关重要。在这方面，有证据表明胰岛素可以对DAT活动产生深刻的调节控制。例如，众所周知，食物限制以及实验诱导的糖尿病对苯丙胺的行为反应都有重大影响。这些观察结果的重要性是由饮食失调和滥用药物的高症同病率强调。最近，据报道，低胰岛素大鼠的DA摄取率降低，并且胰岛素全脑室内应用于大鼠或稳定转染DAT的细胞增加了DA的摄取。重要的是，似乎胰岛素可以干扰苯丙胺在DAT中的作用，并可以防止苯丙胺诱导的DAT内在化。对于本提案而言，特别重要的是，具有苯丙胺自我管理史的糖尿病大鼠显示出增加而不是减少DA摄取。因此，胰岛素及其信号传导途径可能代表开发用于药物滥用的新治疗方法的新目标。迄今为止，尚无研究评估胰岛素在控制体内DAT活动中的作用。由于胰岛素在促进药物的滥用潜力中的潜在影响，因此拟议的研究将使用一种创新的方法，即高速计时仪测量，以测量体内DA外排和清除率的胰岛素依赖性变化。由于胰岛素细胞作用构成的主要信号传导机制是刺激磷脂酰肌醇（PI）-3激酶，这些研究还将检验以下假设：DA EFFIUX和清除将分别增加和降低，而随着PI-3激酶的激活和抑制作用。重要的是，这些研究将确定苯丙胺与DAT活动相关的胰岛素状态的作用之间的关系。我们的总体假设是，DA外排和清除的动力学以及苯丙胺的运动刺激作用将与胰岛素状态密切相关。将胰岛素恢复到正常水平将恢复正常反应。此处获得的结果不仅将改善我们对DAT调节的基本理解，而且重要的是，控制奖励和动机的神经回路，以及为较大的RO1应用提供框架。反过来，这些研究可能有助于阐明饮食失调和滥用药物的高培训的基础神经机制。