Cocaine-Induced Dopamine Transporter Changes are Reversed by Amphetamine

描述(由申请人提供)：可卡因(COC)依赖在美国是一个主要的健康问题，目前还没有批准的药物疗法来帮助治疗。用于成瘾研究的啮齿动物模型的“黄金标准”是COC自我给药。我们已经使用这个模型来表明，长期接触COC会导致多巴胺转运体(DAT)的药效耐受。DAT对COC的耐受性是我们实验室发现的一个较新的现象，这为研究COC耐受性的操纵开辟了一条新的途径，我们将在本提案中进行探索。我们发现，单次注射安非他明(0.56 mg/kg静脉注射)可迅速并完全逆转DAT时的COC耐受性，甚至导致COC效价高于对照水平。具体目标包括对这一发现进行表征和扩展的实验。在特定的目标1中，我们将探索AMPH能引起DAT可塑性逆转的最低有效剂量以及这种效应的时间进程。尽管这一特征相当重要，但我们主要感兴趣的是发现导致这种效应的DAT的结构和功能变化。因此，对于特定的目标2，我们将在结构上使用 用不同DAT亲和力的DA释放剂和阻断剂来代替安非他酮，并使用薄片伏安法来探索COC的效力和突触前DA功能(释放和摄取)对这些化合物的反应。此外，我们对神经化学数据的行为影响很感兴趣。在具体目标3中，我们将在自我给药和运动评估的安慰剂前后对动物进行测试，而另一组将根据COC自我给药的累进比率表进行评估。虽然我们的兴趣主要集中在驱动DAT变化的基本药理学上，但这可能与文献建议的DAT释放剂，如AMPH作为推定的COC成瘾药物疗法有关。尽管针对COC成瘾的激动剂疗法存在争议，但我们或许能够为它们的一些治疗效果定义一个假定的机制，这可能会推动此类疗法的更合理的设计。

DESCRIPTION (provided by applicant): Cocaine (COC) dependence in the United States is a major health problem that currently has no approved pharmacological therapies to help in treatment. The "gold standard" of rodent models used in addiction research is COC self-administration. We have used this model to show that extended exposure to COC results in a pharmacodynamic tolerance of the dopamine transporter (DAT). Tolerance of the DAT to COC is a relatively new phenomenon discovered by our lab, which opened up a new avenue of research into the manipulation of COC tolerance, which we will explore in this proposal. We found that administration of a single AMPH bolus (0.56 mg/kg IV) rapidly and completely reversed the COC tolerance at the DAT, and even caused COC potency to increase above control levels. The specific aims include experiments that characterize and expand on this discovery. In Specific Aim 1 we will explore the lowest effective dose of AMPH that can cause a reversal of DAT plasticity and the time course of this effect. Although this characterization is quite important, we are primarily interested in discovering the structural and functional changes in the DAT that are responsible for this effect. Thus, for Specific Aim 2, we will use structurally different DA releasers and blockers with different DAT affinities in place of an AMPH bolus and use slice voltammetry to explore COC potency and presynaptic DA function (release and uptake) in response to these compounds. Additionally, we are interested in the behavioral implications for our neurochemical data. In Specific Aim 3 we will test animals before and after self-administration and an AMPH bolus with locomotor assessments while another group will be assessed on a progressive ratio schedule of COC self-administration. While our interest is primarily in the basic pharmacology driving the DAT changes, this may be relevant to the literature proposing DAT releasers such as AMPH as putative COC addiction pharmacotherapies. Although agonist therapies for COC addiction are controversial, we may be able to define a putative mechanism for some of their therapeutic effects which could potentially drive more rationale design of such therapies.