Animal models of cocaine addiction

描述（由申请人提供）：可卡因成瘾在北美是一个医疗问题，具有深刻的社会和经济成本。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。动物模型对于评价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。大鼠中的考马斯亮蓝自我给药将用于模拟人类药物服用的这些基本方面。人类药物成瘾的发展是一个过程。我们断言，继续服用药物的动机增加是这个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。在供资初期，确定了两种非常不同的自我管理程序，它们似乎是有助于逐步改变动机的不同机制的模型。增加可卡因强化的断点的现象与成瘾过程的不同阶段有关：（A）诱导阶段：在非常有限的暴露后，动物在测试的前两周内表现出断点的逐步升级。这个模型表明，成瘾过程实际上始于第一次接触毒品。(B)高摄入阶段：每天摄入高水平可卡因的动物表现出非常稳定的可卡因强化断点。如果连续10天不间断地获得可卡因，再加上至少一周不吸毒，这种情况会进一步增加。这个过程模拟了人类成瘾者典型的放纵-禁欲周期。 实验提出，将进一步表征这些现象，并建立剂量-反应关系和时间过程参数。将评估与苯丙胺和甲基苯丙胺的交叉致敏作用。我们的假设是，谷氨酸从前额皮质的预测是重要的发展（但不是表达）的敏化，这将与药理学和病变的研究。

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.