Chen Scott A, O'Dell Laura E, Hoefer Michael E, Greenwell Thomas N, Zorrilla Eric P, Koob George F
Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, CA, USA.
Neuropsychopharmacology. 2006 Dec;31(12):2692-707. doi: 10.1038/sj.npp.1301008. Epub 2006 Jan 25.
The goal of the present study was to develop and validate an animal model of unlimited access to intravenous heroin self-administration combined with responding for food and water to characterize the transition to drug dependence. Male Wistar rats were allowed to lever press for heroin (60 microg/kg/0.1 ml infusion/s; fixed ratio 1; 20-s time out) and nosepoke for food and water in consecutive, daily 23-h sessions. Daily heroin intake increased over days, reaching significance by Day 14. Drug-taking increased across the circadian cycle, reflected as increases in both the nocturnal peak and diurnal nadir of heroin intake. Changes in the circadian pattern of food intake and meal patterning preceded and paralleled the changes in heroin intake. By Day 7, the circadian amplitude of feeding was blunted. Nocturnal intake decreased because rats consumed smaller and briefer meals. Diurnal intake increased due to increased meal frequency, whereas total daily food intake decreased. To control for time or experience in the self-administration boxes as a possible confound, rats with saline (no drug) tethers were tested and did not display significant changes in food intake pattern. Body weight gain slowed slightly in heroin rats relative to saline controls. Separate groups of rats revealed that significant physical dependence as measured by physical signs of opiate withdrawal following a naloxone injection (1.0 mg/kg, subcutaneous (s.c.)) was reached by Day 14. Significant increases in heroin intake could be produced using low doses of naloxone (0.003-0.03 mg/kg, s.c.) on days 28-31 of heroin access. After 6 weeks of heroin self-administration, rats injected with buprenorphine (0, 0.01, 0.04, and 0.2 mg/kg, s.c.) showed a dose-dependent reduction in heroin intake. Changes in the pattern of drug and food intake in the present unlimited heroin access model may serve as independent motivational markers for the transition to a drug-dependent state.
本研究的目的是建立并验证一种动物模型，该模型允许动物无限制地自行静脉注射海洛因，并可通过按压杠杆获取食物和水，以此来表征向药物依赖的转变过程。雄性Wistar大鼠被允许在连续的每日23小时实验时段内，通过按压杠杆获取海洛因（60微克/千克/0.1毫升输注/秒；固定比率1；20秒超时），并通过鼻触获取食物和水。每日海洛因摄入量随时间增加，在第14天达到显著水平。药物摄取在昼夜周期内增加，表现为海洛因摄取的夜间峰值和日间谷底均增加。食物摄入的昼夜模式变化以及进食模式变化先于并与海洛因摄取变化平行。到第7天，进食的昼夜振幅变钝。夜间摄入量减少是因为大鼠进食量更小、时间更短。日间摄入量增加是由于进食频率增加，而每日总食物摄入量减少。为了控制在自行给药箱中的时间或经验这一可能的混杂因素，对连接生理盐水（无药物）的大鼠进行了测试，它们的食物摄入模式没有显著变化。与生理盐水对照组相比，海洛因组大鼠的体重增加略有减缓。单独的几组大鼠显示，在第14天，通过纳洛酮注射（1.0毫克/千克，皮下注射（s.c.））后的阿片戒断体征所测量的显著身体依赖性已经形成。在海洛因给药的第28 - 31天，使用低剂量纳洛酮（0.003 - 0.03毫克/千克，皮下注射）可使海洛因摄入量显著增加。在进行6周的海洛因自行给药后，注射丁丙诺啡（0、0.01、0.04和0.2毫克/千克，皮下注射）的大鼠显示出海洛因摄入量呈剂量依赖性减少。在当前这种无限制获取海洛因的模型中，药物和食物摄入模式的变化可能作为向药物依赖状态转变的独立动机指标。
