Animal models of cocaine addiction

描述(申请人提供)：可卡因成瘾在北美是一个医疗问题，有着巨大的社会和经济代价。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是必不可少的。大鼠体内的可卡因自我给药将被用来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，增加继续服药的动机是这一进程的一个重要方面。 我们的目标一直是开发成瘾过程的动物模型，重点是通过累进比率时间表评估动机的增加。在筹资初期，确定了两种截然不同的自我管理程序，这两种程序似乎模仿了有助于逐步推动变革的不同机制。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，动物在头两周的测试中表现出断点的逐渐增加。这个模型表明，上瘾过程实际上是从第一次接触毒品开始的。(B)高摄入量阶段：每天吸食大量可卡因的动物表现出非常稳定的可卡因强化的转折点。如果将可卡因的全天候供应延长到10天，再加上至少一周的禁药，这种情况可能会进一步增加。这一过程模拟了典型的人类瘾君子的狂欢-禁欲周期。 建议进行实验，进一步描述这些现象，并建立剂量-反应关系和时间进程参数。将评估苯丙胺和甲基苯丙胺的交叉增敏作用。我们的假设是，来自前额叶皮质的谷氨酸投射对于敏化的发展(但不是表达)是重要的，这将通过药理学和损伤研究来解决。

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.