The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, Box 171, New York, NY 10065, USA.
Neuropharmacology. 2012 Aug;63(2):322-9. doi: 10.1016/j.neuropharm.2012.03.021. Epub 2012 Apr 4.
Relapse is a serious problem for the effective treatment of cocaine addiction.
Examining cocaine re-exposure-induced behavioral and neurobiological alterations following chronic escalating-dose binge cocaine administration and withdrawal may provide insight into the neurobiological basis of cocaine relapse.
Our goal was to determine how exposure to chronic escalating-dose cocaine affects development of subsequent cocaine-induced conditioned place preference (CPP) and changes in endogenous opioid systems.
Mice were injected with either escalating-dose binge cocaine (15-30 mg/kg/injection × 3/day) or saline for 14-days and conditioned with 15 mg/kg of cocaine or saline (once per day for 10-days), starting either 1 or 14-days after the last day of binge injections.
Mice exposed to chronic escalating cocaine did not develop CPP to cocaine when conditioning commenced on the first day of withdrawal (CPP test on day 10 of withdrawal). By contrast, mice did develop CPP to cocaine when conditioning started on the 14th day of withdrawal (CPP test on day 24 of withdrawal). Furthermore, preproenkephalin (Penk) mRNA levels in caudate putamen were significantly higher in mice that received 14-day withdrawal from escalating-dose binge cocaine before the CPP procedure (tested 24 days post-binge) than those that received 1-day withdrawal (tested 10 days post-binge).
The rewarding effect of cocaine was blunted in early withdrawal from chronic escalating exposure, but recovered in more prolonged withdrawal. Time-dependent elevations in Penk mRNA levels may be part of the underlying mechanisms of this effect.
复发是可卡因成瘾有效治疗的一个严重问题。
研究慢性递增剂量 binge 可卡因给药和戒断后可卡因再暴露引起的行为和神经生物学改变，可能为可卡因复发的神经生物学基础提供深入了解。
我们的目标是确定慢性递增剂量可卡因暴露如何影响随后可卡因诱导的条件位置偏好（CPP）的发展和内源性阿片系统的变化。
小鼠接受递增剂量 binge 可卡因（15-30 mg/kg/注射×3/天）或生理盐水治疗 14 天，并在 binge 注射的最后一天后 1 或 14 天开始接受 15 mg/kg 的可卡因或生理盐水（每天一次，共 10 天）条件处理。
在戒断的第一天开始条件处理时，暴露于慢性递增可卡因的小鼠对可卡因没有产生 CPP（戒断的第 10 天 CPP 测试）。相比之下，当在戒断的第 14 天开始条件处理时，小鼠确实对可卡因产生了 CPP（戒断的第 24 天 CPP 测试）。此外，在 CPP 程序之前接受 14 天的慢性递增 binge 可卡因戒断后，尾壳核中的前原脑啡肽（Penk）mRNA 水平明显高于那些接受 1 天戒断后接受 CPP 测试（戒断的第 10 天）的小鼠。
在慢性递增暴露的早期戒断期间，可卡因的奖赏效应减弱，但在更长期的戒断中恢复。Penk mRNA 水平的时间依赖性升高可能是这种效应的潜在机制的一部分。
