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

描述（由申请人提供）： 近年来，哌甲酯（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具有滥用潜力，通常在早期发育期间施用，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，有一个显着的缺乏实验数据直接检查口服MPH暴露对随后的可卡因（COC）滥用的影响。这是至关重要的，因为MPH和COC产生类似的行为和神经化学作用，因为COC滥用在ADHD人群中很普遍。在本申请中，提出了在ADHD的自发性高血压大鼠（SHR）模型中检查发育暴露于口服MPH对成年早期COC滥用的脆弱性的作用的实验; Sprague-Dawley大鼠将用作对照。具体目标1将确定在出生后第28-42天（即，青春期前）改变COC对PND 75的运动效应（即，成年早期）。特异性目标2将检测COC自身给药中MPH诱导的变化。在PND 75的单次训练期间，将对MPH处理的大鼠进行训练，以按照固定比率（FR）1时间表自我给予COC。然后，在接下来的14天内，COC输注将根据渐进比例（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。该方案先前已显示产生PR断点的进行性增加（“致敏”），因此在检测COC强化功效中潜在的持久MPH诱导的改变方面应比FR方案更敏感。还将评估食物维持反应，以确定MPH是否选择性地改变COC强化的动机。具体目标3将评估COC对成年早期MPH处理大鼠中脑核（NAcc）和内侧前额叶皮质（mPFC）中多巴胺转运蛋白（DAT）功能的影响。NAcc和mPFC与COC滥用以及ADHD有关;因此，将使用体内伏安法（高速计时电流法）监测全身COC对这些区域中局部应用的多巴胺清除的影响，以确定DAT是否是COC自我给药中潜在MPH诱导变化的底物。总的来说，这些临床前结果应该提供临床相关的信息之间的关联口服MPH暴露在青春期和随后的COC滥用在成年早期。 公共卫生相关性：这些结果也可能有助于开发更安全的ADHD药物，并应加强我们对弱势ADHD人群中COC滥用病因的理解。

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.