Animal models of cocaine addiction

可卡因成瘾的动物模型

• 批准号: 7683288
• 负责人: David Charles Stephen Roberts
• 金额: $ 23.34万
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7683288
• 关键词: Abstinence; Address; Amphetamines; Animal Model; Animals; Cocaine; Cocaine Dependence; Data; Development; Dose; Drug Addiction; Drug Exposure; Excitatory Amino Acid Antagonists; Exposure to; Financial cost; Funding; Glutamates; Goals; Human; Human Development; Injection of therapeutic agent; Intake; Lesion; MK801; Measures; Medical; Methamphetamine; Methods; Modeling; Motivation; N-Methylaspartate; Neurobiology; North America; Pattern; Pharmaceutical Preparations; Phase; Prefrontal Cortex; Procedures; Process; Protocols documentation; Psychological reinforcement; Rattus; Reinforcement Schedule; Relapse; Relative (related person); Research Personnel; Saline; Schedule; Self Administration; Self-Administered; Staging; Substance Abuse Detection; Testing; Therapeutic; Time; Training; addiction; cocaine use; deprivation; experience; programs; research study; response; social

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）：北美的可卡因成瘾是一个医疗问题，具有深远的社会和财务成本。了解可卡因使用的神经生物学后果是发展适当治疗的重要一步。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治疗药物至关重要。可卡因在大鼠中的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，继续服用药物的动力增加是这一过程的重要方面。 我们的目标是开发成瘾过程的动物模型，重点是通过渐进比率时间表评估的动机增加。在资助的最初阶段，确定了两种截然不同的自我管理程序，这些程序似乎对不同的机制进行了建模，从而有助于进行渐进的动机变化。增加可卡因增强的断裂点的现象与成瘾过程的不同阶段有关：（a）诱导阶段：在暴露量非常有限后，动物表明在测试的前两周中，在断裂点逐渐升级。该模型显示成瘾过程几乎是第一次接触药物。 （b）高摄入阶段：经历了高水平每日可卡因的动物表现出非常稳定的可卡因增强的断裂点。通过延长的可卡因可卡因的延长，可以进一步增加10天，再加上至少一周的药物剥夺。该过程模拟了典型的人类成瘾者的暴饮暴食周期。 提出了实验，该实验将进一步表征这些现象并建立剂量反应关系和时间课程参数。将评估与苯丙胺和甲基苯丙胺的交叉敏化。我们的假设是，来自前额叶皮层的谷氨酸投射对于致敏的发展（但不是表达）很重要，这将通过药理学和病变研究来解决。