Dorsal hypothalamic dopaminergic neurons play an inhibitory role in the hypothalamic-pituitary-adrenal axis via activation of D2R in mice
Dorsal hypothalamic dopaminergic neurons play an inhibitory role in the hypothalamic-pituitary-adrenal axis via activation of D2R in mice
复制标题
小鼠下丘脑背侧多巴胺能神经元通过激活 D2R 在下丘脑-垂体-肾上腺轴中发挥抑制作用。
DOI：
10.1111/apha.13187
复制
发表时间：
2019-02-01
影响因子：
6.3
通讯作者：
Chen, Ling
中科院分区：
文献类型：
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作者：
Di, Tingting;Chen, Peipei;Chen, Ling
目的研究下丘脑背侧多巴胺（dh-DA）神经元对成年雄性小鼠下丘脑-垂体-肾上腺（HPA）轴激活的影响。方法分别在信号注射MPTP （20 mg kg(-1)）后4、8、12小时检测酪氨酸羟化酶标记的DA神经元、DA含量、c-Fos免疫阳性（c-Fos+）细胞和室旁核（PVN） CRH表达、血清CORT和ACTH。结果mptp后4小时，PVN内dh-DA神经元和DA含量减少，mptp后12小时恢复，而纹状体内黑质纹状体DA神经元和DA含量从mptp后12小时开始下降。c-Fos+细胞数量和CORT/ACTH水平在mptp后4小时增加，随后在mptp后12小时恢复。mptp后4小时CRH mRNA升高，并持续12小时以上。在mptp后2小时，pvn注射D2R激动剂喹匹罗纠正了c-Fos+细胞、CORT/ACTH和CRH mRNA的升高，但D1R激动剂SKF38393没有。pvn单独注射D2R拮抗剂l -舒匹利可引起c-Fos+细胞、CORT/ACTH和CRH mRNA升高。同样，pvn注射CB1R激动剂WIN552,12可以阻止c-Fos+细胞和CORT/ACTH的增加，而不是CRH mRNA的增加，这是被CB1R拮抗剂AM251阻断的。mptp后4小时PVN中PKA和CREB磷酸化水平升高，可被喹匹罗阻断，但不被win52,12阻断。PKA抑制剂H89在mptp后8小时纠正CRH mRNA的升高。结论dh-DA神经元的激活通过靶向CRH神经元的D2Rs负性调节HPA轴，增强内源性大麻素的释放，抑制PKA-CREB通路。
Aim The present study investigated the effects of dorsal hypothalamic dopamine (dh-DA) neurons on activation of hypothalamic-pituitary-adrenal (HPA) axis in adult male mice. Methods Tyrosine hydroxylase-labelled DA neurons, DA content, c-Fos immune-positive (c-Fos+) cells and CRH expression in paraventricular nuclei (PVN), serum CORT and ACTH were examined at 4-, 8-, and 12-hour after a signal injection of MPTP (20 mg kg(-1)) respectively. Results The dh-DA neurons and DA content in PVN at 4-hour post-MPTP were reduced with recovery at 12-hour post-MPTP, while decline of nigrostriatal DA neurons and DA content in striatum started from 12-hour post-MPTP. Number of c-Fos+ cells, and CORT/ACTH levels increased at 4-hour post-MPTP, followed by recovery at 12-hour post-MPTP. The CRH mRNA was elevated at 4-hour post-MPTP, and sustained for over 12 hours. At 2-hour post-MPTP, PVN-injection of D2R agonist quinpirole corrected the increases in c-Fos+ cells, CORT/ACTH and CRH mRNA, but D1R agonist SKF38393 did not. PVN-injection of D2R antagonist L-sulpiride alone caused increases in c-Fos+ cells, CORT/ACTH and CRH mRNA. Similarly, PVN-injection of CB1R agonist WIN552,12 prevented the increases in c-Fos+ cells and CORT/ACTH rather than CRH mRNA, which were blocked by CB1R antagonist AM251. Levels of PKA and CREB phosphorylation in PVN were increased at 4-hour post-MPTP, which were blocked by quinpirole, but not WIN552,12. PKA inhibitor H89 corrected the increase of CRH mRNA at 8-hour post-MPTP. Conclusion The activation of dh-DA neurons regulates negatively HPA axis through targeting D2Rs of CRH neurons to enhance endocannabinoid release and inhibit PKA-CREB pathway.