Heroin self-administration in dependent Wistar rats: increased sensitivity to naloxone
Heroin self-administration in dependent Wistar rats: increased sensitivity to naloxone
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DOI：
10.1007/s002130050983
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发表时间：
1999-05-01
影响因子：
3.4
通讯作者：
Koob, GF
中科院分区：
文献类型：
--
作者：
Carrera, MRA;Schulteis, G;Koob, GF
基本原理：非依赖性和依赖性阿片类药物使用者似乎是由两个不同的动机因素驱动的：药物的主要强化特性，以及与缓解依赖状态下阿片类药物戒断的负面情感成分相关的负面强化效应。目的：探讨阿片依赖对海洛因自我给药（HSA）的动机意义。研究方法：训练大鼠自我静脉注射海洛因（0.06 mg/kg/输注; FR 1），并通过皮下植入两个吗啡（75 mg碱）丸诱导阿片依赖。非依赖性对照组的大鼠接受安慰剂颗粒。植入颗粒后3天，每天3小时恢复HSA，直至达到基线标准，并在治疗115分钟内皮下注射溶媒或纳洛酮（0、0.003、0.01、0.03 mg/kg）进行试验。结果：吗啡依赖大鼠经0.01 mg/kg纳洛酮治疗后，血清白蛋白水平显著升高，但0.03 mg/kg纳洛酮治疗后，反应率降低。在0.01和0.03 mg/kg剂量下，植入安慰剂颗粒的大鼠增加了海洛因摄入量。在第二个实验中，HSA疗程缩短至1小时，在新的动物组中，训练剂量降低至每次输注0.03 mg/kg。安慰剂颗粒植入大鼠中的HSA仅在最高剂量的拮抗剂后增加，而依赖性大鼠仍然受到0.003-0.03 mg/kg纳洛酮剂量的影响。当进行累进比率计划（实验3）时，依赖性动物的临界点值高于基线198%。结论：本研究支持这一假设，即吗啡颗粒植入大鼠的依赖性诱导导致对非常小剂量纳洛酮的敏感性增加，如通过HSA的变化所测量的。综上所述，这些数据表明，阿片类药物依赖，作为衡量纳洛酮的敏感性变化，是一个连续体，可以促进药物寻求的动机状态。
Rationale: Non-dependent and dependent opiate users appear to be driven by two distinct motivational factors: the primary reinforcing properties of the drug, and the negative reinforcing effects associated with relieving the negative affective component of opiate withdrawal in the dependent state. Objective: To investigate the motivational significance of opioid dependence on heroin self-administration (HSA) in rodents. Methods: Rats were trained to self-administer heroin intravenously (0.06 mg/kg per infusion; FR1), and opiate dependence was induced by subcutaneous implantation of two morphine (75 mg base) pellets. Rats in a non-dependent control group received placebo pellets. Three days after pellet implantation, HSA was resumed in daily 3-h sessions until baseline criteria were met and testing was conducted with subcutaneous injections of vehicle or naloxone (0, 0.003, 0.01, 0.03 mg/kg) 115 min into the session. Results: Morphine-dependent rats significantly increased HSA upon 0.01 mg/kg naloxone treatment, but decreased response rates at 0.03 mg/kg. Placebo pellet-implanted rats increased heroin intake at the 0.01 and 0.03 mg/kg doses. In a second experiment, the HSA session was shortened to 1 h and the training dose reduced to 0.03 mg/kg per infusion in new groups of animals. HSA in placebo pellet-implanted rats was increased only following the highest dose of the antagonist, while dependent rats were still affected by naloxone doses of 0.003-0.03 mg/kg. When subjected to a progressive-ratio schedule (experiment 3), breaking point values in dependent animals were 198% above baseline. Conclusions: The present study supports the hypothesis that dependence-induction by morphine-pellet implant in rats resulted in increased sensitivity to very small naloxone doses, as measured by changes in HSA. Taken together, these data suggest that opiate dependence, as measured by changes in sensitivity to naloxone, is a continuum which can contribute to the motivational state of drug-seeking.