Effects of Chronic Stress on Cocaine and Food Relapse: Role of Dopamine D1-Like R

项目摘要 药物成瘾是一种慢性疾病，其特点是复发率高，即使在很长一段时间后， 戒毒期同样，饮食治疗的长期成功率也很低，因为 大多数人在开始治疗后的几个月内会重新养成不健康的饮食习惯。因此，我们认为， 调查环境因素和神经机制，增加一个人的脆弱性， 复发是至关重要的发展，改善治疗战略，这些主要的公共卫生 问题来自临床文献的证据表明，复发通常是由暴露于 应力使用动物复发模型，已经表明急性暴露于药理学 应激物育亨宾诱导大鼠药物和可口食物寻求复发。但没有 就长期压力对复发的影响进行了系统的研究。因为人类 暴露于多种压力源，急性和慢性，重要的是要了解的作用， 慢性应激在复发易感性中的作用，以及慢性应激和急性应激之间的相互作用 在测试中恢复。考虑到急性应激和急性应激引起的行为缺陷 应激诱发复发涉及内侧前额叶皮层多巴胺D1受体介导的传递， 我们假设，在药物戒断或饮食限制期间， 一个人的脆弱性复发，而且这种影响是由多巴胺能机制介导的。测试 在这些假设中，老鼠将被训练按下可卡因或可口食物的杠杆， 行为随后将被消除。为了模拟慢性应激，每天给大鼠注射 育亨宾（0.0或5.0 mg/kg × 10天;腹膜内），或置于限制器中（3小时/天× 10天）。评估 多巴胺能参与，慢性应激将与系统性或内侧前额叶皮质相结合 输注SCH-23390（分别为0.0或10.0 μ g/kg和0.0、0.5或1.0 μ g/侧），多巴胺D1样 受体拮抗剂在慢性应激之后，将测试大鼠的可卡因或吗啡的恢复。 由急性育亨宾（0.0、1.0或2.0 mg/kg; i. p.）可卡因或食物引发我们 初步数据表明，我们的方法是可行的，它可以成功地用作工具， 研究慢性应激对复发影响的神经药理学机制。

Project Summary Drug addiction is a chronic disorder characterized by high rates of relapse, even after long periods of abstinence from drug use. Similarly, long-term success of dietary treatments is low because most individuals relapse to unhealthy eating habits within months of starting treatment. Therefore, investigations into the environmental factors and neural mechanisms that increase one's vulnerability to relapse are critical to the development of improved treatment strategies for these major public health problems. Evidence from the clinical literature suggests that relapse is often triggered by exposure to stress. Using an animal relapse model, it has been shown that acute exposure to the pharmacological stressor yohimbine induces relapse to both drug and palatable food seeking in rats. However, no systematic studies on the effects of chronic stress on relapse have been conducted. Because humans are exposed to multiple stressors, both acutely and chronically, it is important to understand the role of chronic stress in relapse vulnerability, as well as the interaction between chronic stress and acute stress during testing on reinstatement. Given that both the behavioral deficits due to acute stress and acute stress-induced relapse involve dopamine D1 receptor-mediated transmission in medial prefrontal cortex, we hypothesize that chronic exposure to stress during drug abstinence or dietary restriction increases one's vulnerability to relapse, and also that this effect is mediated by dopaminergic mechanisms. To test these hypotheses, rats will be trained to press a lever for cocaine or palatable food reinforcers, and the behavior will subsequently be extinguished. To model chronic stress, rats will be injected daily with yohimbine (0.0 or 5.0 mg/kg x 10 days; i.p.), or placed in restrainers (3 h/day x 10 days). To assess dopaminergic involvement, chronic stress will be combined with systemic or intra-medial prefrontal cortex infusions of SCH-23390 (0.0 or 10.0 ¿g/kg and 0.0, 0.5, or 1.0 ¿g/side, respectively), a dopamine D1-like receptor antagonist. Subsequent to chronic stress, rats will be tested for reinstatement of cocaine or food seeking triggered by acute yohimbine (0.0, 1.0, or 2.0 mg/kg; i.p.) and cocaine or food priming. Our preliminary data indicate that our approach is feasible, and that it can be used successfully as a tool for investigating the neuropharmacological mechanisms of chronic stress effects on relapse.