Early Drug Exposure and Drug Reward Mechanisms

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，使其成为最普遍的儿童疾病。多动症可以有效地治疗兴奋剂，包括哌醋甲酯（MPH; RitalinTM），这是间接多巴胺（DA）激动剂，他们的使用正在上升。然而，由于担心这类兴奋剂被滥用或可能成为滥用其他药物的“通道”，这类兴奋剂的使用受到限制。最近的临床数据显示，与未接受药物治疗的儿童相比，接受兴奋剂治疗的ADHD儿童的药物滥用减少了85%。然而，这些临床观察结果的解释是困难的，因为有效治疗的ADHD患者改善了心理社会和学术技能，减少了其他风险因素，如社会障碍。此外，他们没有解决潜在的机制，导致替代的解释，包括可能性，早期治疗与MPH可以印记的基础神经生物学底物的兴奋剂滥用。换句话说，青少年暴露于MPH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间。 这些问题中的一些可能可以使用动物模型来回答，并且已经表明，长期暴露于兴奋剂药物，如MPH，会导致奖励效应的长期增加，从而增加对药物滥用的脆弱性。然而，这些研究是在成年动物中进行的，限制了其对幼龄（发育中）大脑药物治疗的解释。因此，我们开发了一种动物模型，使用MPH暴露在幼年大鼠。在这个模型中，MPH暴露使中等剂量的可卡因令人厌恶，高剂量的可卡因在以后的生活中不那么有益，表明对兴奋剂滥用的脆弱性降低。因此，我们的研究结果表明，印记和/或年龄的差异，MPH的药代动力学可能介导其持久的影响。在拟议的一组研究中，我们奋进确定：1）年龄相关的贡献的生物利用度的MPH可卡因奖励以后的生活; 2）慢性MPH治疗对多巴胺释放的影响在青春期前大鼠; 3）是否青春期前暴露于MPH改变多巴胺受体的表达;和4）多巴胺的作用在MPH诱导的变化在青春期前大鼠的潜在机制。

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.