Reinforcing and neurochemical effects of cocaine in a rodent model of ADHD

描述（由申请人提供）：近年来，哌醋甲酯（MPH）用于治疗注意力缺陷/多动障碍（ADHD）的使用有所增加。然而，MPH有滥用的可能性，并且通常在发育早期使用，这引发了一些担忧，即早期MPH暴露可能会增加以后生活中药物滥用的风险。尽管如此，明显缺乏直接检查口服MPH暴露对随后可卡因（COC）滥用影响的实验数据。这是至关重要的，因为MPH和COC产生相似的行为和神经化学作用，因为COC滥用在ADHD人群中很普遍。本研究拟在自发性高血压大鼠（SHR） ADHD模型中研究发育性暴露于口服MPH对成年早期COC滥用易感的作用；Sprague-Dawley大鼠作为对照。特异性目的1将确定在产后28-42天（即青春期周围）反复口服MPH是否会改变COC对PND 75（即成年早期）的运动效果。特异性目标2将测试mph诱导的COC自我给药的改变。mph治疗的大鼠将在PND 75的单次训练期间，按照固定比例（FR） 1时间表进行自我服用COC的训练。然后，在接下来的14天内，COC输注将按照递进比（PR）计划进行，以评估发育性MPH暴露后COC自我给药的动机方面。该方案先前已被证明会产生PR断点的渐进式增加（“致敏”），因此在检测潜在的持久mph诱导的COC增强功效的改变方面，应该比FR方案更敏感。还将评估食物维持的反应，以确定MPH是否选择性地改变COC强化的动机。特异性目的3将评估COC对成年早期mph处理大鼠伏隔核（NAcc）和内侧前额叶皮层（mPFC）多巴胺转运体（DAT）功能的影响。NAcc和mPFC与COC滥用和ADHD有关；因此，系统性COC对这些区域局部施加的多巴胺清除的影响将通过体内伏安法（高速计时安培法）进行监测，以确定DAT是否是mph诱导COC自我给药的潜在改变的底物。总的来说，这些临床前结果应该为青春期口服MPH暴露与成年早期随后的COC滥用之间的关系提供临床相关信息。

DESCRIPTION (provided by applicant): The use of methylphenidate (MPH) for the treatment of attention-deficit/hyperactivity disorder (ADHD) has increased in recent years. However, MPH has abuse potential and is typically administered during early development, prompting some concern that early MPH exposure may increase the risk for substance abuse later in life. Despite of this, there is a notable lack of experimental data directly examining the influence of oral MPH exposure on subsequent cocaine (COC) abuse. This is critical because MPH and COC produce similar behavioral and neurochemical effects, and because COC abuse is prevalent in the ADHD population. In the present application, experiments are proposed to examine the role of developmental exposure to oral MPH on vulnerability for COC abuse in early adulthood in the spontaneously-hypertensive rat (SHR) model of ADHD; Sprague-Dawley rats will be used as controls. Specific Aim 1 will determine whether repeated oral MPH administration during postnatal days (PND) 28-42 (i.e., periadolescence) alters the locomotor effect of COC on PND 75 (i.e., early adulthood). Specific Aim 2 will test for MPH-induced alterations in COC self administration. MPH-treated rats will be trained to self-administer COC under a fixed ratio (FR) 1 schedule during a single training session on PND 75. Then, over the next 14 days, COC infusions will be available under a progressive ratio (PR) schedule to assess motivational aspects of COC self-administration following developmental MPH exposure. This protocol has been shown previously to produce progressive increases ('sensitization') of PR breakpoints, and should therefore be more sensitive than FR schedules for detecting potential enduring MPH-induced alterations in the reinforcing efficacy of COC. Food-maintained responding will also be assessed to determine whether MPH selectively alters motivation for COC reinforcement. Specific Aim 3 will assess the effect of COC on dopamine transporter (DAT) function in the nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC) of MPH-treated rats in early adulthood. The NAcc and mPFC are implicated in COC abuse as well as ADHD; thus, the effect of systemic COC on clearance of locally-applied dopamine in these regions will be monitored with in vivo voltammetry (high-speed chronoamperometry) in order to determine whether DAT is a substrate for potential MPH-induced alterations n COC self-administration. Collectively, these preclinical results should provide clinically-relevant information on the association between oral MPH exposure during adolescence and subsequent COC abuse in early adulthood. PUBLIC HEALTH RELEVANCE: These results may also aid the development of safer ADHD medications and should enhance our understanding of the etiology of COC abuse in the vulnerable ADHD population.