BACKGROUND Compulsive patterns of drug use are thought to be the consequence of drug-induced adaptations in the neural mechanisms that enable behavior to be flexible. Neuroimaging studies have found evidence of robust alterations in glutamate and dopamine receptors within brain regions that are known to be critical for decision-making processes in cocaine-dependent individuals, and these changes have been argued to be the consequence of persistent drug use. The causal relationships among drug-induced alterations, cocaine taking, and maladaptive decision-making processes, however, are difficult to establish in humans. METHODS We assessed decision making in adult male rats using a probabilistic reversal learning task and used positron emission tomography with the [11C]-(+)-PHNO and [18F]FPEB radioligands to quantify regional dopamine D2/3 and metabotropic glutamate 5 (mGlu5) receptor availability, respectively, before and after 21 days of cocaine or saline self-administration. Tests of motivation and relapse-like behaviors were also conducted. RESULTS We found that self-administration of cocaine, but not of saline, disrupted behavior in the probabilistic reversal learning task measured by selective impairments in negative-outcome updating and also increased cortical mGlu5 receptor availability following 2 weeks of forced abstinence. D2/3 and, importantly, midbrain D3 receptor availability was not altered following 2 weeks of abstinence from cocaine. Notably, the degree of the cocaine-induced increase in cortical mGlu5 receptor availability was related to the degree of disruption in negative-outcome updating. CONCLUSIONS These findings suggest that cocaine-induced changes in mGlu5 signaling may be a mechanism by which disruptions in negative-outcome updating emerge in cocaine-dependent individuals.

中文翻译：

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与 mGlu5 相关的决策失调，但与中脑 D3 无关，大鼠可卡因自我给药后的受体可用性

背景技术药物使用的强迫模式被认为是药物诱导的神经机制适应的结果，这种适应使行为变得灵活。神经影像学研究发现，大脑区域内谷氨酸和多巴胺受体发生强烈变化的证据，这些变化对依赖可卡因的个体的决策过程至关重要，而这些变化被认为是持续吸毒的结果。然而，药物引起的改变、可卡因服用和适应不良的决策过程之间的因果关系很难在人类身上建立。方) 受体可用性，分别在可卡因或盐水自我给药 21 天之前和之后。还进行了动机和类似复发行为的测试。结果我们发现，可卡因的自我给药，而不是盐水的自我给药，破坏了概率逆转学习任务中的行为，通过消极结果更新的选择性损伤来衡量，并且在强制禁欲 2 周后皮质 mGlu5 受体的可用性增加。戒断可卡因 2 周后，D2/3 和重要的是中脑 D3 受体的可用性没有改变。尤其，可卡因诱导的皮质 mGlu5 受体可用性增加的程度与负面结果更新的中断程度有关。结论 这些研究结果表明，可卡因诱导的 mGlu5 信号传导变化可能是可卡因依赖个体中出现负面结果更新中断的机制。