Animal models of cocaine addiction

描述（由申请人提供）：可卡因成瘾在北美是一个具有深刻社会和经济代价的医学问题。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是必不可少的。大鼠的可卡因自我给药将用于模拟人类服药的这些基本方面。人类吸毒成瘾的发展是一个过程。我们断言，继续服用药物的动机的增加是这一过程的一个重要方面。

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.