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

描述(由申请人提供)：近年来，用于治疗注意力缺陷/多动障碍(ADHD)的哌醋甲酯(MPH)的使用有所增加。然而，mph具有滥用的可能性，通常在发育早期使用，这引发了一些人的担忧，即早期接触mph可能会增加以后生活中药物滥用的风险。尽管如此，明显缺乏直接检验口服公共卫生对随后的可卡因(COC)滥用的影响的实验数据。这一点至关重要，因为MPH和COC产生相似的行为和神经化学效应，而且COC滥用在ADHD人群中很普遍。在目前的应用中，我们计划在ADHD的自发性高血压大鼠(SHR)模型中，研究发育过程中暴露于口服PMH对成年早期COC滥用的易感性的作用；将以SpragueDawley大鼠作为对照。具体目标1将确定在出生后28-42天(即青春期前)重复口服MPH是否会改变COC对PND 75(即成年期早期)的运动效应。特定目标2将测试公共卫生诱导的COC自我给药变化。在PND 75的单次训练过程中，MPH处理的大鼠将被训练成在固定比率(FR)1时间表下自我给药COC。然后，在接下来的14天里，将按照累进比率(PR)计划进行COC输注，以评估发育中的公共卫生暴露后COC自我管理的激励方面。该方案先前已被证明可产生PR断点的渐进性增加(“敏化”)，因此在检测PMH诱导的COC增强效果的潜在持久变化方面应比FR方案更敏感。食物维持的反应也将被评估，以确定公共卫生是否选择性地改变COC强化的动机。具体目标3将评估COC对成年早期MPH处理的大鼠伏隔核(NAcc)和内侧前额叶皮质(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，将用体内伏安法(高速计时电流法)监测全身COC对这些区域局部应用的多巴胺清除的影响，以确定DAT是否为COC自我给药中MPH诱导的潜在改变的底物。总而言之，这些临床前研究结果应该提供青春期口服PMH暴露与成年早期滥用COC之间的联系的临床相关信息。 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，并应加强我们对易受伤害的ADHD人群中COC滥用的病因的理解。

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.