Early Drug Exposure and Drug Reward Mechanisms

描述(由申请人提供)：注意力缺陷/多动障碍(ADHD)影响大约6%的学龄儿童的注意力和运动能力，使其成为最常见的儿童障碍。ADHD可以用包括哌醋甲酯(MPH；Ritalin TM)在内的兴奋剂有效治疗，这是一种间接的多巴胺(DA)激动剂，其使用量正在上升。然而，由于担心这类兴奋剂的滥用或它们可能作为滥用其他物质的“门户”的作用，这类兴奋剂的使用一直受到限制。最近的临床数据显示，与那些没有接受药物治疗的儿童相比，接受兴奋剂治疗的ADHD儿童经历的药物滥用减少了85%。然而，这些临床观察很难解释，因为有效治疗的ADHD患者改善了心理社会和学习技能，减少了其他风险因素，如社会损害。此外，它们没有解决导致替代解释的潜在机制，包括早期使用mph治疗可能会在兴奋剂滥用的潜在神经生物学底物上留下印记。换句话说，青少年接触PMH可能会对发育中的大脑的神经生物学产生持久的影响，这种影响超过了药物治疗本身的时期。 其中一些问题可能可以用动物模型来回答，而且已经表明，长期接触刺激性药物，如MPH，会导致奖励效应的长期增加，从而增加对药物滥用的易感性。然而，这些研究是在成年动物身上进行的，限制了他们对青少年(发育中)大脑的药物治疗的解释。因此，我们开发了一种在幼年大鼠身上使用MPH暴露的动物模型。在这个模型中，暴露在公共卫生水平使中等剂量的可卡因令人厌恶，而高剂量的可卡因在晚年回报较少，表明对兴奋剂滥用的易感性降低。因此，我们的结果表明，mph药代动力学的印迹和/或年龄差异可能调节其持久效应。在拟议的一系列研究中，我们试图确定：1)MPH的生物利用度对晚年可卡因奖励的年龄相关贡献；2)慢性MPH治疗对青春期前大鼠多巴胺释放的影响；3)青春期前暴露于MPH是否改变了多巴胺受体的表达；以及4)多巴胺在MPH诱导的青春期前大鼠变化的潜在机制中的作用。

DESCRIPTION (provided by applicant): Attention-deficit/hyperactivity disorder (ADHD) affects attention and motor capacities in approximately 6% of school-aged children, making it the most prevalent childhood disorder. ADHD can be treated effectively with stimulants including methylphenidate (MPH; RitalinTM), which are indirect dopamine (DA) agonists, and their use is rising. However, the use of such stimulants has been limited by concerns over their abuse or the possible role they play as a "gateway" to the abuse of other substances. Recent clinical data show that ADHD children treated with stimulants experience an 85% reduction in substance abuse compared with those who do not receive pharmacotherapy. The interpretation of these clinical observations, however, is difficult since effectively treated ADHD patients have improved psychosocial and academic skills that reduce other risk factors, such as social impairment. In addition, they do not address potential mechanisms leading to alternative interpretations including the possibility that early treatment with MPH can imprint on the underlying neurobiological substrate of stimulant abuse. In other words, juvenile exposure to MPH potentially can produce enduring effects on the neurobiology of the developing brain that outlast the period of drug treatment itself. Some of these questions can potentially be answered using animal models and it has been shown that chronic exposure to stimulant drugs, such as MPH, causes long-lasting increases in rewarding effects, thereby increasing vulnerability to substance abuse. However, these studies have been performed in adult animals limiting their interpretation for drug treatment in juvenile (developing) brains. We have, therefore, developed an animal model using MPH exposure in juvenile rats. In this model, MPH exposure made moderate doses of cocaine aversive and high doses less rewarding later in life demonstrating reduced vulnerability to stimulant abuse. Thus, our results indicate that imprinting and/or age differences in pharmacokinetics of MPH could mediate its enduring effects. In the proposed set of studies we endeavor to determine: 1) the age-related contribution of bioavailability of MPH to cocaine reward later in life; 2) the effect of chronic MPH treatment on dopamine release in the pre-pubertal rat; 3) whether pre-pubertal exposure to MPH changes dopamine receptor expression; and 4) the role of dopamine in the underlying mechanism of MPH-induced changes in the pre-pubertal rat.