Inserm UMR-S839, France.
Sorbonne Université, Université Pierre et Marie Curie (UPMC), France.
Addict Biol. 2019 May;24(3):364-375. doi: 10.1111/adb.12600. Epub 2018 Jan 10.
Conditioned place preference (CPP) is widely used for evaluating the rewarding effects of drugs. Like other memories, CPP is proposed to undergo reconsolidation during which it is unstable and sensitive to pharmacological inhibition. Previous studies have shown that cocaine CPP can be apparently erased by extracellular signal-regulated kinase (ERK) pathway inhibition during cocaine reconditioning (re-exposure to the drug-paired environment in the presence of the drug). Here, we show that blockade of D1 receptors during reconditioning prevented ERK activation and induced a loss of CPP. However, we also unexpectedly observed a CPP disappearance in mice that underwent testing and reconditioning with cocaine alone, specifically in strong conditioning conditions. The loss was due to the intermediate test. CPP was not recovered with reconditioning or priming in the short term, but it spontaneously reappeared after a month. When we challenged the D1 antagonist-mediated erasure, we observed that both a high dose of cocaine and a first CPP test were required for this effect. Our results also suggest a balance between D1-dependent ERK pathway activation and an A2a-dependent mechanism in D2 striatal neurons in controlling CPP expression. Our data reveal that, paradoxically, a simple CPP test can induce a complete (but transient) loss of place preference following strong but not weak cocaine conditioning. This study emphasizes the complex nature of CPP memory and the importance of multiple parameters that must be taken into consideration when investigating reconsolidation.
条件位置偏爱（CPP）被广泛用于评估药物的奖赏效应。与其他记忆一样，CPP 被提议在再巩固期间经历不稳定和对药理学抑制敏感。先前的研究表明，在可卡因再条件作用（在药物存在的情况下重新暴露于药物配对环境）期间，细胞外信号调节激酶（ERK）途径的抑制可以明显消除可卡因 CPP。在这里，我们表明，在再条件作用期间阻断 D1 受体可以防止 ERK 激活并诱导 CPP 的丧失。然而，我们也出乎意料地观察到，在单独使用可卡因进行测试和再条件作用的小鼠中，尤其是在强烈的条件作用条件下，CPP 消失了。这种损失是由于中间测试。在短期内，CPP 不会通过再条件作用或引发恢复，但一个月后会自发重新出现。当我们挑战 D1 拮抗剂介导的擦除时，我们观察到这种效应需要高剂量可卡因和第一次 CPP 测试。我们的结果还表明，D2 纹状体神经元中的 D1 依赖性 ERK 途径激活和 A2a 依赖性机制之间存在平衡，控制 CPP 的表达。我们的数据表明，矛盾的是，在强烈但不是弱可卡因条件作用后，简单的 CPP 测试会导致位置偏爱完全（但短暂）丧失。这项研究强调了 CPP 记忆的复杂性，以及在研究再巩固时必须考虑多个参数的重要性。
