Buprenorphine and a CRF1 Antagonist Block the Acquisition of Opiate Withdrawal-Induced Conditioned Place Aversion in Rats
Buprenorphine and a CRF1 Antagonist Block the Acquisition of Opiate Withdrawal-Induced Conditioned Place Aversion in Rats
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DOI：
10.1038/sj.npp.1300487
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发表时间：
2005
影响因子：
7.6
通讯作者：
L. Stinus;M. Cador;E. Zorrilla;G. Koob
中科院分区：
文献类型：
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作者：
L. Stinus;M. Cador;E. Zorrilla;G. Koob
大鼠条件性位置厌恶具有表面效度，可作为阿片类药物戒断的厌恶性刺激效应的量度，反映了阿片类药物依赖的重要动机成分。本研究的目的是验证条件性位置厌恶敏感的药物，这将减轻阿片类药物戒断的厌恶刺激的影响，在人类，并扩展该模型的阿片类药物戒断的动机影响的神经药理学基础的探索。雄性Sprague-Dawley大鼠皮下植入两个吗啡丸，5天后皮下给予低剂量纳洛酮后开始位置条件反射训练。动物接受三组低剂量纳洛酮（15 μg/kg，sc）与三室位置调节装置的一个臂的配对。丁丙诺啡在每次配对前给药，剂量依赖性地阻断了由阿片类药物戒断引起的位置厌恶。促肾上腺皮质激素释放因子-1（CRF 1）受体拮抗剂（antalarmin）也逆转了阿片类药物戒断引起的位置厌恶。Antalarmin本身并没有在吗啡依赖大鼠中产生位置偏好或位置厌恶。预先给予多巴胺部分激动剂特桂胺或选择性5-羟色胺再摄取抑制剂氟西汀均无影响。此外，阿坎酸（一种用于防止酒精依赖复发的谷氨酸受体调节剂）的慢性预处理并没有改变纳洛酮诱导的位置厌恶。丁丙诺啡本身在依赖性大鼠中产生了低剂量的轻度位置偏好和高剂量的轻度位置厌恶。这些结果表明，丁丙诺啡块沉淀阿片类药物戒断大鼠的厌恶性刺激作用，并提供了一些有效性的使用位置条件反射作为一种措施，是敏感的潜在阿片类药物依赖。此外，这些结果表明，CRF 1拮抗剂可以阻断阿片戒断的厌恶性刺激效应，并可能成为阿片依赖的潜在治疗靶点。
Conditioned place aversion in rats has face validity as a measure of the aversive stimulus effects of opiate withdrawal that reflects an important motivational component of opiate dependence. The purpose of the present study was to validate conditioned place aversion as sensitive to medications that will alleviate the aversive stimulus effects of opiate withdrawal in humans, and to extend this model to the exploration of the neuropharmacological basis of the motivational effects of opiate withdrawal. Male Sprague–Dawley rats were implanted with two subcutaneous morphine pellets and 5 days later began place conditioning training following subcutaneous administration of a low dose of naloxone. Animals were subjected to three pairings of a low dose of naloxone (15 μg/kg, sc) to one arm of a three-chambered place conditioning apparatus. Buprenorphine administered prior to each pairing dose-dependently blocked the place aversion produced by precipitated opiate withdrawal. A corticotropin-releasing factor-1 (CRF 1) receptor antagonist (antalarmin) also reversed the place aversion produced by precipitated opiate withdrawal. Antalarmin did not produce a place preference or place aversion by itself in morphine-dependent rats. No effect was observed with pretreatment of the dopamine partial agonist terguride or the selective serotonin reuptake inhibitor fluoxetine. Also, chronic pretreatment with acamprosate (a glutamate receptor modulator used to prevent relapse in alcohol dependence) did not alter naloxone-induced place aversion. Buprenorphine by itself in dependent rats produced a mild place preference at low doses and a mild place aversion at higher doses. These results suggest that buprenorphine blocks the aversive stimulus effects of precipitated opiate withdrawal in rats and provides some validity for the use of place conditioning as a measure that is sensitive to potential opiate-dependence medications. In addition, these results suggest that CRF 1 antagonists can block the aversive stimulus effects of opiate withdrawal and may be potential therapeutic targets for opiate dependence.