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

可卡因在 ADHD 啮齿动物模型中的强化和神经化学作用

• 批准号: 7619180
• 负责人: THOMAS E WOOTERS
• 金额: $ 2.95万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-24 至 2010-03-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7619180
• 关键词: Adolescence; Amphetamines; Attention deficit hyperactivity disorder; Behavioral; Brain region; Catheters; Clinical; Cocaine; Cocaine Abuse; Data; Development; Dopamine; Dose; Etiology; Exhibits; Exposure to; Food; Human; Implant; Inbred SHR Rats; Infusion procedures; Life; Medial; Methylphenidate; Modeling; Monitor; Motivation; Nucleus Accumbens; Oral; Oral Administration; Pharmaceutical Preparations; Population; Prefrontal Cortex; Protocols documentation; Psychological reinforcement; Rat Strains; Rattus; Relative (related person); Risk; Rodent Model; Role; Route; Schedule; Self Administration; Self-Administered; Specificity; Speed; Sprague-Dawley Rats; Substance abuse problem; Techniques; Testing; Therapeutic; Time; Training; Work; clinically relevant; density; dopamine transporter; drug abuser; emerging adult; in vivo; neurochemistry; non-drug; postnatal; pre-clinical; public health relevance; reinforced behavior; reinforcer; relating to nervous system; research study; response

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.

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）的用途有所增加。然而，MPH 具有滥用的可能性，并且通常在早期发育期间施用，这引发了一些担忧，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 MPH 暴露对随后可卡因 (COC) 滥用影响的实验数据。这一点至关重要，因为 MPH 和 COC 会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。在本申请中，提出了实验来检验在 ADHD 自发性高血压大鼠 (SHR) 模型中，发育性暴露于口服 MPH 对成年早期 COC 滥用脆弱性的作用； Sprague-Dawley 大鼠将用作对照。具体目标 1 将确定出生后 (PND) 28-42（即青春期）期间重复口服 MPH 是否会改变 COC 对 PND 75（即成年早期）的运动作用。具体目标 2 将测试 MPH 诱导的 COC 自我给药变化。在 PND 75 的单次训练期间，MPH 治疗的大鼠将接受训练，按照固定比例 (FR) 1 时间表自我施用 COC。然后，在接下来的 14 天中，COC 输注将按照渐进比例 (PR) 时间表进行，以评估发育性 MPH 暴露后 COC 自我施用的动机方面。该方案先前已被证明可以产生 PR 断点的逐渐增加（“敏化”），因此应该比 FR 时间表更敏感，用于检测 COC 增强功效中潜在的持久 MPH 诱导的变化。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。具体目标 3 将评估 COC 对成年早期接受 MPH 治疗的大鼠伏隔核 (NAcc) 和内侧前额皮质 (mPFC) 的多巴胺转运蛋白 (DAT) 功能的影响。 The NAcc and mPFC are implicated in COC abuse as well as ADHD;因此，系统性COC对这些区域局部应用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COC自我给药中潜在的MPH诱导改变的底物。总的来说，这些临床前结果应提供有关青春期口服 MPH 暴露与随后成年早期 COC 滥用之间关系的临床相关信息。 公共健康相关性：这些结果也可能有助于开发更安全的 ADHD 药物，并应增强我们对易受影响的 ADHD 人群中 COC 滥用病因的了解。