Regulation of σ-1 Receptors and Endoplasmic Reticulum Chaperones in the Brain of Methamphetamine Self-Administering Rats
Regulation of σ-1 Receptors and Endoplasmic Reticulum Chaperones in the Brain of Methamphetamine Self-Administering Rats
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DOI：
10.1124/jpet.109.159244
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发表时间：
2010-03-01
影响因子：
3.5
通讯作者：
Su, Tsung-Ping
中科院分区：
文献类型：
--
作者：
Hayashi, Teruo;Justinova, Zuzana;Su, Tsung-Ping
σ-1受体是内质网（ER）分子伴侣，其涉及与精神兴奋剂滥用相关的神经可塑性。我们用免疫细胞化学方法检测了未用药大鼠大脑中sigma-1受体的分布，然后检测了自我给药甲基苯丙胺、被动接受甲基苯丙胺或仅接受生理盐水注射的大鼠特定大脑亚区中sigma-1受体和其他ER分子伴侣的动态。发现σ-1受体在嗅球、纹状体、丘脑核壳、嗅结节、杏仁核、海马、红核、腹侧被盖区、黑质和蓝斑中以中等至高水平表达。甲基苯丙胺，无论是自我管理或被动接受，显着升高ER分子伴侣，包括σ-1受体，BiP，和钙网蛋白在腹侧被盖区和黑质。然而，在嗅球中，只有sigma-1受体伴侣蛋白增加，这种增加只发生在主动自我给药甲基苯丙胺的大鼠中。与σ-1受体的增加一致，发现细胞外信号调节激酶被激活，蛋白激酶A在甲基苯丙胺自我给药大鼠的嗅球中减弱。发现嗅球中的σ-1受体与多巴胺D1受体共定位。这些结果表明，甲基苯丙胺诱导内质网应激腹侧被盖区和黑质在大鼠是否接受药物是主动或被动的。然而，只有在大鼠积极自我管理甲基苯丙胺的变化表明，D1和sigma-1受体在嗅球可能发挥重要作用的动机条件反射/学习方面的甲基苯丙胺自我管理的大鼠。
sigma-1 Receptors are endoplasmic reticulum (ER) chaperones that are implicated in the neuroplasticity associated with psychostimulant abuse. We immunocytochemically examined the distribution of sigma-1 receptors in the brain of drug-naive rats and then examined the dynamics of sigma-1 receptors and other ER chaperones in specific brain subregions of rats that self-administered methamphetamine, received methamphetamine passively, or received only saline injections. sigma-1 Receptors were found to be expressed in moderate to high levels in the olfactory bulb, striatum, nucleus accumbens shell, olfactory tubercle, amygdala, hippocampus, red nucleus, ventral tegmental area, substantia nigra, and locus ceruleus. Methamphetamine, whether self-administered or passively received, significantly elevated ER chaperones including the sigma-1 receptor, BiP, and calreticulin in the ventral tegmental area and substantia nigra. In the olfactory bulb, however, only the sigma-1 receptor chaperone was increased, and this increase occurred only in rats that actively self-administered methamphetamine. Consistent with an increase in sigma-1 receptors, extracellular signal-regulated kinase was found to be activated and protein kinase A attenuated in the olfactory bulb of methamphetamine self-administering rats. sigma-1 Receptors in the olfactory bulb were found to be colocalized with dopamine D1 receptors. These results indicate that methamphetamine induces ER stress in the ventral tegmental area and substantia nigra in rats whether the drug is received actively or passively. However, the changes seen only in rats that actively self-administered methamphetamine suggest that D1 and sigma-1 receptors in the olfactory bulb might play an important role in the motivational conditioning/learning aspects of methamphetamine self-administration in the rat.