Amphetamine Sensitization: Role of Dopamine Transporters

描述(由申请人提供)： 反复接触精神刺激药物通常会导致行为敏化，这指的是在服用相同或更低剂量的药物后，运动反应增强。这种现象在戒毒后会持续很长时间，已经被认为是导致人类吸毒成瘾的各个方面的原因，包括对毒品的渴求和复发。在这里提出的研究中，我将探讨多巴胺转运体(DAT)功能在行为敏化表达中的作用。DAT负责清除细胞外间隙中的DA。使用近交系Lewis和Fischer 344大鼠，分别被描述为成瘾倾向和抗成瘾，我将使用定量放射自显影测量体外放射配基结合和体内高速计时电流法测量外源性DA的清除，以测量纹状体和伏隔核中DAT的数量和功能。将在未经治疗的大鼠和那些每天停止静脉注射生理盐水或安非他明(AMPH)的大鼠身上进行测量。这些近交系大鼠在纹状体和伏隔核中表达的DAT数量基本不同，但尚不清楚这是否导致DAT功能的不同。我将特别注意对表达敏感性的个体差异与以下所有因素的相关性：DSTR、NAC及其各自亚区的DAT数量，这些区域的基础DAT活性，以及频繁应用DA和/或全身AMPH调节DAT功能的能力。这些实验将有助于阐明DAT在行为敏化中的作用，并进一步了解与重复药物摄入相关的神经适应。

DESCRIPTION (provided by applicant): Repeated exposure to psychostimulant drugs typically leads to behavioral sensitization, which refers to enhanced motor responsiveness after administration of the same or lower doses of the drug. This phenomenon, which persists well after drug taking ceases, has been suggested to contribute to various aspects of human drug addiction, including "craving" and relapse. In the research proposed here, I will investigate the role of dopamine transporter (DAT) function in the expression of behavioral sensitization. The DAT is responsible for clearing DA from the extracellular space. Using inbred Lewis and Fischer 344 rats, which have been described as addiction-prone and addiction-resistant, respectively, I will measure DAT number and function in the striatum and nucleus accumbens using quantitative autoradiography to measure in vitro radioligand binding and in vivo high-speed chronoamperometry to measure clearance of exogenous DA. Measurements will be made in untreated rats and those withdrawn from daily intravenous injections of saline or amphetamine (AMPH). These inbred rat strains exhibit basal differences in the number of DATs expressed in striatum and nucleus accumbens, but it is not clear if this leads to differences in DAT function. I will pay particular attention to correlation between individual differences in the susceptibility to express sensitization and all of the following: DAT number in dSTR, NAc and their respective subregions, basal DAT activity in these areas, and the ability of either frequent DA application and/or systemic AMPH to regulate DAT function. These experiments will help elucidate the role of the DAT in behavioral sensitization and further our understanding of the neuroadaptations associated with repeated drug intake.