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首页> 外文期刊>The European Journal of Neuroscience >The fragile X mental retardation protein promotes adjustments in cocaine self-administration that preserve reinforcement level
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The fragile X mental retardation protein promotes adjustments in cocaine self-administration that preserve reinforcement level

机译：脆弱的X精神迟滞蛋白促进了可卡因自我管理的调整，以保持加固水平

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摘要

The fragile X mental retardation protein (FMRP), an RNA-binding protein, regulates cocaine-induced neuronal plasticity and is critical for the normal development of drug-induced locomotor sensitization, as well as reward-related learning in the conditioned place preference assay. However, it is unknown whether FMRP impacts behaviors that are used to more closely model substance use disorders. Utilizing a cocaine intravenous self-administration (IVSA) assay in Fmr1 knockout (KO) and wild-type (WT) littermate mice, we find that, despite normal acquisition and extinction learning, Fmr1 KO mice fail to make a normal upward shift in responding during dose-response testing. Later, when given access to the original acquisition dose under increasing fixed ratio (FR) schedules of reinforcement (FR1, FR3, and FR5), Fmr1 KO mice earn significantly fewer cocaine infusions than WT mice. Importantly, similar deficits are not present in operant conditioning using a palatable food reinforcer, indicating that our results do not represent broad learning or reward-related deficits in Fmr1 KO mice. Additionally, we find an FMRP target, the activity-regulated cytoskeleton-associated protein (Arc), to be significantly reduced in synaptic cellular fractions prepared from the nucleus accumbens of Fmr1 KO, compared with WT, mice following operant tasks reinforced with cocaine but not food. Overall, our findings suggest that FMRP facilitates adjustments in drug self-administration behavior that generally serve to preserve reinforcement level, and combined with our similar IVSA findings in Arc KO mice may implicate Arc, along with FMRP, in behavioral shifts that occur in drug taking when drug availability is altered.
机译：脆性X智力低下蛋白（FMRP）是一种RNA结合蛋白，调节可卡因诱导的神经元可塑性，对药物诱导的运动敏化的正常发展以及条件性位置偏爱分析中的奖赏相关学习至关重要。然而，目前尚不清楚FMRP是否会影响用于更密切模拟物质使用障碍的行为。在Fmr1基因敲除（KO）和野生型（WT）同窝小鼠中使用可卡因静脉注射自我给药（IVSA）分析，我们发现，尽管Fmr1基因敲除小鼠具有正常的获得和灭绝学习能力，但在剂量-反应测试中，Fmr1基因敲除小鼠的反应未能正常向上移动。后来，当在递增固定比率（FR）强化计划（FR1、FR3和FR5）下获得原始获取剂量时，Fmr1 KO小鼠获得的可卡因输注量明显少于WT小鼠。重要的是，在使用美味食物增强剂的操作性条件反射中没有出现类似的缺陷，这表明我们的结果并不代表Fmr1-KO小鼠的广泛学习或奖赏相关缺陷。此外，我们发现，与WT小鼠相比，Fmr1-KO伏隔核突触细胞组分中的FMRP靶点，即活性调节细胞骨架相关蛋白（Arc），在进行可卡因而非食物强化的操作性任务后显著减少。总的来说，我们的研究结果表明，FMRP有助于药物自我给药行为的调整，这通常有助于维持强化水平，并且结合我们在Arc-KO小鼠中的类似IVSA研究结果，可能暗示Arc和FMRP在药物可得性改变时在服药过程中发生的行为改变中。

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