ProSAAS-derived peptides are regulated by cocaine and are required for sensitization to the locomotor effects of cocaine
ProSAAS-derived peptides are regulated by cocaine and are required for sensitization to the locomotor effects of cocaine
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DOI：
10.1111/jnc.14209
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发表时间：
2017-11-01
影响因子：
4.7
通讯作者：
Fricker, Lloyd D.
中科院分区：
文献类型：
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作者：
Berezniuk, Iryna;Rodriguiz, Ramona M.;Fricker, Lloyd D.
为了确定受可卡因调节的神经肽，我们使用定量多肽分析技术，检测了小鼠每天10 mg/kg可卡因或生理盐水连续7天后，小鼠脑内几个区域神经肽的相对水平。在伏隔核、尾壳核、额叶皮质和腹侧被盖区的一个或多个大脑区域共鉴定出102种不同的多肽。在尾壳核或额叶皮质中检测到的任何多肽都不会因可卡因的注射而改变。在可卡因处理的小鼠中，伏隔核中的三种多肽和腹侧被盖区的七种多肽显着减少。这十种多肽中有五种来源于ProSAAS，它是一种分泌途径蛋白和神经肽前体。为了研究proSAAS多肽是否参与了精神刺激剂的生理效应，我们在野外用野生型(WT)和proSAAS基因敲除(KO)小鼠检测了可卡因和苯丙胺的急性反应。与这两种精神刺激剂的突变小鼠相比，WT组小鼠的运动受到更强烈的刺激。在ProSAAS KO小鼠中，对苯丙胺的行为敏感度没有保持，这些突变体也未能对可卡因敏化。为了确定可卡因的奖赏效应是否发生了改变，对小鼠进行了条件性位置偏爱(CPP)测试。WT和ProSAAS KO小鼠对可卡因都表现出剂量依赖性的CPP，但没有按基因区分。综上所述，这些结果表明，proSAAS衍生的多肽对心理刺激剂的行为敏化有不同的贡献，而在缺乏proSAAS的小鼠中，可卡因的奖赏效应似乎是完整的。
To identify neuropeptides that are regulated by cocaine, we used a quantitative peptidomic technique to examine the relative levels of neuropeptides in several regions of mouse brain following daily intraperitoneal administration of 10mg/kg cocaine or saline for 7days. A total of 102 distinct peptides were identified in one or more of the following brain regions: nucleus accumbens, caudate putamen, frontal cortex, and ventral tegmental area. None of the peptides detected in the caudate putamen or frontal cortex were altered by cocaine administration. Three peptides in the nucleus accumbens and seven peptides in the ventral tegmental area were significantly decreased in cocaine-treated mice. Five of these ten peptides are derived from proSAAS, a secretory pathway protein and neuropeptide precursor. To investigate whether proSAAS peptides contribute to the physiological effects of psychostimulants, we examined acute responses to cocaine and amphetamine in the open field with wild-type (WT) and proSAAS knockout (KO) mice. Locomotion was stimulated more robustly in the WT compared to mutant mice for both psychostimulants. Behavioral sensitization to amphetamine was not maintained in proSAAS KO mice and these mutants failed to sensitize to cocaine. To determine whether the rewarding effects of cocaine were altered, mice were tested in conditioned place preference (CPP). Both WT and proSAAS KO mice showed dose-dependent CPP to cocaine that was not distinguished by genotype. Taken together, these results suggest that proSAAS-derived peptides contribute differentially to the behavioral sensitization to psychostimulants, while the rewarding effects of cocaine appear intact in mice lacking proSAAS.