Bumetanide treatment during early development rescues maternal separation-induced susceptibility to stress
Bumetanide treatment during early development rescues maternal separation-induced susceptibility to stress
复制标题
早期发育期间的布美他尼治疗可挽救母体分离引起的压力敏感性
DOI：
10.1038/s41598-017-12183-z
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发表时间：
2017-09-19
影响因子：
4.6
通讯作者：
Shi, Jie
中科院分区：
文献类型：
--
作者：
Hu, Die;Yu, Zhou-Long;Shi, Jie
压力是精神疾病的主要危险因素，如抑郁症、创伤后应激障碍和精神分裂症。早期生活压力，如母亲分离，可能对中枢神经系统的发育和精神疾病的发病机制产生长期影响。在本研究中，我们发现母亲分离增加了青春期大鼠对应激的易感性，增加了出生后14天海马中Na+/K+/2Cl（-）协同转运蛋白1（NKCC 1）的表达，增加了出生后40天海马中K+/2Cl（-）协同转运蛋白2（KCC 2）和γ-氨基丁酸A（GABA（A））受体亚单位的表达。在出生后的前两周内，美国食品和药物管理局批准的药物布美他尼抑制NKCC 1可以挽救由母亲分离诱导的抑郁和焦虑样行为，并降低海马中NKCC 1，KCC 2和GABA（A）受体α 1和β 2，3亚基的表达。在早期发育过程中，布美他尼给药不会对未处理大鼠的体重或正常行为产生不良影响，也不会影响成年大鼠的血清渗透压。这些结果表明，布美他尼治疗在早期发展可能会防止母体分离诱导的应激和海马GABA能传递障碍的易感性。
Stress is a major risk factor for psychiatric disorders, such as depression, posttraumatic stress disorder, and schizophrenia. Early life stress, such as maternal separation, can have long-term effects on the development of the central nervous system and pathogenesis of psychiatric disorders. In the present study, we found that maternal separation increased the susceptibility to stress in adolescent rats, increased the expression of Na+/K+/2Cl(-) cotransporter 1 (NKCC1) on postnatal day 14, and increased the expression of K+/2Cl(-) cotransporter 2 (KCC2) and gamma-aminobutyric acid A (GABA(A)) receptor subunits on postnatal day 40 in the hippocampus. NKCC1 inhibition by the U.S. Food and Drug Administration-approved drug bumetanide during the first two postnatal weeks rescued the depressive-and anxiety-like behavior that was induced by maternal separation and decreased the expression of NKCC1, KCC2 and GABA(A) receptor alpha 1 and beta 2,3 subunits in the hippocampus. Bumetanide treatment during early development did not adversely affect body weight or normal behaviors in naive rats, or affect serum osmolality in adult rats. These results suggest that bumetanide treatment during early development may prevent the maternal separation-induced susceptibility to stress and impairments in GABAergic transmission in the hippocampus.