Imetronic®, Marcheprime, France.
Université de Bordeaux, UFR des Sciences Odontologiques, Bordeaux, France.
Neuropsychopharmacology. 2022 Jan;47(2):444-453. doi: 10.1038/s41386-021-01159-3. Epub 2021 Aug 24.
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.
药物成瘾的一个行为特征是，尽管意识到这会导致负面后果，但仍继续使用药物。在动物中模拟这一特征的典型方法是用电击脚来惩罚药物自我给药，以确定哪些个体的药物使用受到惩罚的抑制程度不同。在这里，我们试图进一步研究在静脉注射可卡因自我给药的大鼠中，药物使用对惩罚的个体反应性。首先，大鼠在数周内接受训练，根据固定比率 3 的强化方案自我给予可卡因。然后，用逐渐增强的电击强度（即 0.1 mA 至 0.9 mA，每 30 分钟一次）来惩罚他们的自我给药行为。随着惩罚强度的增加，大鼠首先继续自我给予可卡因，然后最终几乎完全停止。然而，当重新测试时，药物使用对惩罚变得更加敏感，并被低强度且最初无效的电击（即 0.1 mA）所抑制。所有接受测试的个体都表现出这种对惩罚的反应性增加，尽管程度不同，但这种增加是在单次经历接近完全抑制药物自我给药的惩罚强度后获得的。然而，仅仅被动地、非偶然地暴露于相同的强度并没有这种效果。一旦获得，增加对惩罚的反应性在至少一个月内持续存在，当大鼠每周测试一次，但不是每天测试一次时。最后，在暴露于非疼痛形式的惩罚（即组胺）后，没有观察到增加对惩罚的反应性。总的来说，这项研究表明，药物使用对惩罚的初始反应性可以随着经验的积累而迅速和持久地变化。我们讨论了几种可能的机制，可以解释这种惩罚反应性的变化，并探讨了一些对强迫样行为动物模型研究的启示和未来展望。
