Animal models of cocaine addiction

可卡因成瘾的动物模型

• 批准号: 7127170
• 负责人: David Charles Stephen Roberts
• 金额: $ 24.52万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7127170
• 关键词: AMPA receptors; NMDA receptors; amphetamines; behavioral habituation /sensitization; chordate locomotion; circadian rhythms; cocaine; disease /disorder model; dosage; drug /alcohol abstinence; drug addiction; eating; inhibitor /antagonist; laboratory rat; methamphetamine; model design /development; motivation; pathologic process; prefrontal lobe /cortex; psychopathology; psychopharmacology; reinforcer; relapse /recurrence; self medication

DESCRIPTION (provided by applicant): Cocaine addiction in North America is a medical problem with profound social and financial cost. Understanding the neurobiological consequences of cocaine use is an important step in the development of appropriate treatments. An animal model is essential for evaluating the underlying neurobiology of drug abuse and for testing potentially therapeutic drugs. Cocaine self-administration in rats will be used to model these fundamental aspects of human drug taking. The development of human drug addiction is a process. We assert that increases in motivation to continue taking the drug is an important aspect of this process. Our goal has been to develop animal models of the addiction process, with a focus on increases in motivation assessed by a progressive ratio schedule. During the initial period of funding two very different self-administration procedures were identified which appear to model different mechanisms which contribute to a progressive motivational change. The phenomena which increase cocaine-reinforced break points are associated with different phases of the addiction process: (A) Induction phase: after very limited exposure animals demonstrate a progressive escalation in break points over the first two weeks of testing. This model shows the addiction process begins with virtually the first exposure to drug. (B) High intake phase: animals that have experienced high levels of daily cocaine show remarkably stable cocaine-reinforced break points. These can be further increased with extended round-the-clock access to cocaine for 10 days plus a drug deprivation of at least a week. This procedure models binge-abstinence cycles typical of human addicts. Experiments are proposed that will further characterize these phenomena and establish dose-response relationships and time course parameters. Cross-sensitization with amphetamine and methamphetamine will be assessed. Our hypothesis is that glutamate projections from the prefrontal cortex is important for the development (but not the expression) of sensitization and this will be addressed with pharmacological and lesion studies.

描述（由申请人提供）：在北美，可卡因成瘾是一个造成严重社会和经济损失的医学问题。了解可卡因使用的神经生物学后果是开发适当治疗方法的重要一步。动物模型对于评估药物滥用的潜在神经生物学和测试潜在的治疗药物至关重要。大鼠的可卡因自我给药将用于模拟人类吸毒的这些基本方面。人类毒瘾的发展是一个过程。我们断言，增加继续服用药物的动力是这一过程的一个重要方面。 我们的目标是开发成瘾过程的动物模型，重点是通过渐进比例计划评估动机的增加。在资助的最初阶段，确定了两种截然不同的自我管理程序，它们似乎模拟了有助于渐进式动机改变的不同机制。可卡因强化断点增加的现象与成瘾过程的不同阶段有关： (A) 诱导阶段：在非常有限的接触后，动物在测试的前两周内表现出断点逐渐升高。该模型表明成瘾过程实际上是从第一次接触毒品开始的。 (B) 高摄入阶段：每日摄入高浓度可卡因的动物表现出非常稳定的可卡因强化折点。如果连续 10 天全天候获取可卡因，再加上至少一周戒毒，这些数字可以进一步增加。该程序模拟了人类成瘾者典型的暴饮暴食周期。 提出的实验将进一步表征这些现象并建立剂量反应关系和时程参数。将评估与苯丙胺和甲基苯丙胺的交叉过敏。我们的假设是，前额皮质的谷氨酸投射对于敏化的发展（但不是表达）很重要，这将通过药理学和病变研究来解决。