Homer proteins regulate sensitivity to cocaine
Homer proteins regulate sensitivity to cocaine
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DOI：
10.1016/j.neuron.2004.07.019
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发表时间：
2004-08-05
期刊：
影响因子：
16.2
通讯作者：
Kalivas, PW
中科院分区：
文献类型：
--
作者：
Szumlinski, KK;Dehoff, MH;Kalivas, PW
药物成瘾涉及遗传易感个体的药理学和学习之间复杂的相互作用。荷马基因家族的成员受到急性和慢性可卡因施用的调节。在这里，我们报告，小鼠中 Homer1 或 Homer:2 的缺失导致对可卡因诱导的运动、条件奖励和伏核中细胞外谷氨酸增加的敏感性与重复可卡因戒断所引起的敏感性相同。此外，腺相关病毒介导的Homer2 KO小鼠伏隔核中Homer2的恢复逆转了可卡因致敏表型。对 Homer2 KO 小鼠的进一步分析揭示了与可卡因敏感动物广泛的额外行为和神经化学相似性，包括加速获得可卡因自我给药以及通过代谢型谷氨酸受体和胱氨酸/谷氨酸交换改变谷氨酸调节。这些数据表明，荷马缺失模仿了重复服用可卡因所产生的行为和神经化学表型，并表明荷马在调节可卡因成瘾中发挥着作用。
Drug addiction involves complex interactions between pharmacology and learning in genetically susceptible individuals. Members of the Homer gene family are regulated by acute and chronic cocaine administration. Here, we report that deletion of Homer1 or Homer:2 in mice caused the same increase in sensitivity to cocaine-induced locomotion, conditioned reward, and augmented extracellular glutamate in nucleus accumbens as that elicited by withdrawal from repeated cocaine administration. Moreover, adeno-associated virus-mediated restoration of Homer2 in the accumbens of Homer2 KO mice reversed the cocaine-sensitized phenotype. Further analysis of Homer2 KO mice revealed extensive additional behavioral and neurochemical similarities to cocaine-sensitized animals, including accelerated acquisition of cocaine self-administration and altered regulation of glutamate by metabotropic glutamate receptors and cystine/glutamate exchange. These data show that Homer deletion mimics the behavioral and neurochemical phenotype produced by repeated cocaine administration and implicate Homer in regulating addiction to cocaine.