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首页> 外文期刊>The European Journal of Neuroscience >Paradoxical tolerance to cocaine after initial supersensitivity in drug-use-prone animals
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Paradoxical tolerance to cocaine after initial supersensitivity in drug-use-prone animals

机译：易吸毒动物对初始超敏反应后对可卡因的悖论耐受

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摘要

There is great interest in outlining biological factors and behavioral characteristics that either predispose or predict vulnerability to substance use disorders. Response to an inescapable novel environment has been shown to predict a "drug-use-prone" phenotype that is defined by rapid acquisition of cocaine self-administration. Here, we showed that response to novelty can also predict the neurochemical and behavioral effects of acute and repeated cocaine in rats. We used cocaine self-administration under a fixed-ratio 1 schedule followed by fast-scan cyclic voltammetry in brain slices to measure subsecond dopamine (DA) release and uptake parameters in drug-use-prone and -resistant phenotypes. Despite no significant differences in stimulated release and uptake, animals with high responses to a novel environment had DA transporters that were more sensitive to cocaine-induced uptake inhibition, which corresponded to greater locomotor activating effects of cocaine. These animals also acquired cocaine self-administration more rapidly and, after 5 days of extended access cocaine self-administration, high-responding animals showed robust tolerance to DA uptake inhibition by cocaine. The effects of cocaine remained unchanged in animals with low novelty responses. Similarly, the rate of acquisition was negatively correlated with DA uptake inhibition by cocaine after self-administration. Thus, we showed that tolerance to the cocaine-induced inhibition of DA uptake coexists with a behavioral phenotype that is defined by increased preoccupation with cocaine as measured by rapid acquisition and early high intake.
机译：概述倾向于或预测易受物质使用障碍影响的生物学因素和行为特征引起了极大的兴趣。已显示出对不可避免的新型环境的反应可预测“可吸毒”表型，该表型是通过快速获得可卡因自我给药而定义的。在这里，我们表明对新颖性的反应也可以预测大鼠急性和反复可卡因的神经化学和行为效应。我们使用固定比例1时间表的可卡因自我给药，然后在脑片中进行快速扫描循环伏安法，以测量易用和耐药表型中亚秒多巴胺（DA）的释放和摄取参数。尽管在刺激释放和摄取方面无显着差异，但对新环境具有高响应的动物的DA转运蛋白对可卡因诱导的摄取抑制更为敏感，这对应于可卡因的更大的运动激活作用。这些动物还更快地获得了可卡因自我给药，并且在延长接触可卡因自我给药5天后，高反应性动物表现出对可卡因抑制DA摄取的强大耐受性。可卡因的影响在具有低新奇反应的动物中保持不变。同样，在自用后，可卡因的获取速率与可卡因对DA的吸收抑制呈负相关。因此，我们表明，对可卡因诱导的DA摄取抑制的耐受性与行为表型并存，该行为表型由快速摄取和早期高摄入量所衡量，可卡因的摄入量增加。

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