Ghasemzadeh M Behnam, Windham Lindsay K, Lake Russell W, Acker Christopher J, Kalivas Peter W
Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconson 53233, USA.
Synapse. 2009 Jan;63(1):42-53. doi: 10.1002/syn.20577.
Homer proteins are intracellular scaffolding proteins that, among glutamate receptors, selectively bind to group1 metabotropic glutamate receptors and regulate their trafficking and intracellular signaling. Homer proteins have been implicated in synaptic and behavioral plasticity, including drug-seeking behavior after cocaine treatment. Homer1 gene activation leads to transcription of a variant mRNA (Homer1a), which functions as an immediate early gene. Homer1a competes with the constitutive Homer proteins (Homer1b/c/d, Homer2a/b, Homer3) for binding to group1 metabotropic glutamate and IP3 receptors. Binding of Homer1a to these proteins disrupts their association with the intracellular signaling scaffold and modulates receptor function. In this study, using RT-PCR, activation of Homer1a mRNA transcription in response to acute and repeated administration of cocaine was characterized in prefrontal cortex, nucleus accumbens, and ventral tegmental area, three mesocorticolimbic nuclei of the rat brain. Moreover, the dopaminergic and glutamatergic regulation of Homer1 gene activation by cocaine was investigated. Acute cocaine rapidly and transiently activated transcription of Homer1a mRNA in all three nuclei. However, repeated administration of cocaine was not effective in inducing the Homer1a mRNA transcription after various withdrawal times ranging from 2 h to 3 weeks. The acute cocaine-mediated activation of Homer1 gene was regulated by D1 but not D2 dopamine receptors. The blockade of AMPA or NMDA glutamate receptors did not prevent cocaine-mediated activation of Homer1 gene in the three mesocorticolimbic nuclei. These data indicate that acute administration of cocaine transiently activates Homer1 gene producing the immediate early gene Homer1a mRNA in the three mesocorticolimbic nuclei of the rat brain. Activation of Homer1 gene may contribute to the cocaine-mediated synaptic and behavioral plasticity.
荷马蛋白是细胞内支架蛋白，在谷氨酸受体中，它能选择性地与1型代谢型谷氨酸受体结合，并调节其运输和细胞内信号传导。荷马蛋白与突触和行为可塑性有关，包括可卡因治疗后的觅药行为。荷马1基因的激活导致一种可变mRNA（荷马1a）的转录，该mRNA作为即刻早期基因发挥作用。荷马1a与组成型荷马蛋白（荷马1b/c/d、荷马2a/b、荷马3）竞争结合1型代谢型谷氨酸和IP3受体。荷马1a与这些蛋白的结合会破坏它们与细胞内信号支架的关联，并调节受体功能。在本研究中，使用逆转录聚合酶链反应（RT-PCR），对大鼠脑的三个中脑边缘核即前额叶皮质、伏隔核和腹侧被盖区中，急性和反复给予可卡因后荷马1a mRNA转录的激活情况进行了表征。此外，还研究了可卡因对荷马1基因激活的多巴胺能和谷氨酸能调节。急性给予可卡因能迅速且短暂地激活所有三个核中荷马1a mRNA的转录。然而，在2小时至3周的不同戒断时间后，反复给予可卡因并不能有效诱导荷马1a mRNA的转录。急性可卡因介导的荷马1基因激活受D1而非D2多巴胺受体调节。AMPA或NMDA谷氨酸受体的阻断并不能阻止可卡因介导的三个中脑边缘核中荷马1基因的激活。这些数据表明，急性给予可卡因能短暂激活荷马1基因，在大鼠脑的三个中脑边缘核中产生即刻早期基因荷马1a mRNA。荷马1基因的激活可能有助于可卡因介导的突触和行为可塑性。
