Calipari Erin S, Siciliano Cody A, Zimmer Benjamin A, Jones Sara R
1] Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA [2] Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Neuropsychopharmacology. 2015 Feb;40(3):728-35. doi: 10.1038/npp.2014.238. Epub 2014 Sep 12.
Although traditional sensitization paradigms, which result in an augmentation of cocaine-induced locomotor behavior and dopamine (DA) overflow following repeated experimenter-delivered cocaine injections, are often used as a model to study drug addiction, similar effects have been difficult to demonstrate following cocaine self-administration. We have recently shown that intermittent access (IntA) to cocaine can result in increased cocaine potency at the DA transporter (DAT); however, traditional sensitization paradigms often show enhanced effects following withdrawal/abstinence periods. Therefore, we determined a time course of IntA-induced sensitization by examining the effects of 1 or 3 days of IntA, as well as a 7-day abstinence period on DA function, cocaine potency, and reinforcement. Here we show that cocaine potency is increased following as little as 3 days of IntA and further augmented following an abstinence period. In addition, IntA plus abstinence produced greater evoked DA release in the presence of cocaine as compared with all other groups, demonstrating that following abstinence, both cocaine's ability to increase DA release and inhibit uptake at the DAT, two separate mechanisms for increasing DA levels, are enhanced. Finally, we found that IntA-induced sensitization of the DA system resulted in an increased reinforcing efficacy of cocaine, an effect that was augmented after the 7-day abstinence period. These results suggest that sensitization of the DA system may have an important role in the early stages of drug abuse and may drive the increased drug seeking and taking that characterize the transition to uncontrolled drug use. Human data suggest that intermittency, sensitization, and periods of abstinence have an integral role in the process of addiction, highlighting the importance of utilizing pre-clinical models that integrate these phenomena, and suggesting that IntA paradigms may serve as novel models of human addiction.
尽管传统的致敏范式（在实验者反复注射可卡因后会导致可卡因诱导的运动行为增强和多巴胺（DA）溢出）常被用作研究药物成瘾的模型，但在可卡因自我给药后，类似的效果却难以得到证实。我们最近发现，间歇性接触（IntA）可卡因会导致DA转运体（DAT）处的可卡因效力增加；然而，传统的致敏范式在戒断期后往往会显示出增强的效果。因此，我们通过检查1天或3天的IntA以及7天的戒断期对DA功能、可卡因效力和强化作用的影响，确定了IntA诱导的致敏的时间进程。在这里，我们表明，仅3天的IntA后可卡因效力就会增加，在戒断期后会进一步增强。此外，与所有其他组相比，IntA加戒断在存在可卡因的情况下产生了更大的诱发DA释放，这表明在戒断后，可卡因增加DA释放和抑制DAT摄取（增加DA水平的两种独立机制）的能力都增强了。最后，我们发现IntA诱导的DA系统致敏导致可卡因的强化效力增加，这种效果在7天的戒断期后增强。这些结果表明，DA系统的致敏可能在药物滥用的早期阶段起重要作用，并可能推动药物寻求和使用的增加，这是向不受控制的药物使用转变的特征。人类数据表明，间歇性、致敏和戒断期在成瘾过程中具有不可或缺的作用，突出了利用整合这些现象的临床前模型的重要性，并表明IntA范式可能作为人类成瘾的新模型。
