One behavioral feature of drug addiction is continued drug use despite awareness that this causes negative consequences. Attempts to model this feature in animals typically involve punishing drug self-administration with electrical footshock to identify individuals whose drug use is differently suppressed by punishment. Here we sought to further study individual responsiveness of drug use to punishment in rats self-administering intravenous cocaine. Rats were first trained during several weeks to self-administer cocaine under a fixed-ratio 3 schedule of reinforcement. Then, their self-administration behavior was punished with increasing intensity of footshock (i.e., from 0.1 mA to 0.9 mA, every 30 min). With increasing intensity of punishment, rats first continued to self-administer cocaine before eventually stopping near completely. When retested, however, drug use became more responsive to punishment and was suppressed by a low and initially ineffective footshock intensity (i.e., 0.1 mA). This increase in responsiveness to punishment was seen in all individuals tested, albeit with varying degrees, and was acquired after one single experience with an intensity of punishment that near completely suppressed drug self-administration. Mere passive, non-contingent exposure to the same intensity, however, had no such effect. Once acquired, increased responsiveness to punishment persisted during at least one month when rats were tested every week, but not every day. Finally, increased responsiveness to punishment was not observed after exposure to a non-painful form of punishment (i.e., histamine). Overall, this study reveals that initial responsiveness of drug use to punishment can change rapidly and persistently with experience. We discuss several possible mechanisms that may account for this change in punishment responsiveness and also draw some of the implications and future perspectives for research on animal models of compulsion-like behavior.

吸毒成瘾的一个行为特征是继续吸毒，尽管意识到这会导致负面后果。尝试在动物身上模拟这种特征通常涉及用电击来惩罚药物自我管理，以识别其药物使用因惩罚而受到不同抑制的个体。在这里，我们试图进一步研究药物使用对大鼠自我静脉注射可卡因的惩罚的个体反应。在数周内首先训练大鼠在固定比率 3 的强化计划下自行服用可卡因。然后，他们的自我管理行为受到越来越强的电击（即从 0.1 毫安到 0.9 毫安，每 30 分钟）的惩罚。随着惩罚强度的增加，老鼠首先继续自我服用可卡因，然后最终几乎完全停止。复试时，然而，药物使用对惩罚变得更加敏感，并被较低且最初无效的电击强度（即 0.1 毫安）抑制。这种对惩罚反应的增加在所有接受测试的人身上都可以看到，尽管程度不同，并且是在一次经历了几乎完全抑制药物自我管理的强烈惩罚之后获得的。然而，仅仅被动地、非偶然地暴露在相同的强度下，没有这样的效果。一旦获得，对惩罚的反应增强会持续至少一个月，每周对老鼠进行测试，但不是每天都对它们进行测试。最后，在暴露于非痛苦形式的惩罚（即组胺）后，未观察到对惩罚的反应增加。全面的，这项研究表明，药物使用对惩罚的初始反应会随着经验的变化而迅速而持久地发生变化。我们讨论了可能解释这种惩罚反应变化的几种可能机制，并得出了一些对类似强迫行为的动物模型研究的影响和未来前景。