Leptin receptor deficiency confers resistance to behavioral effects of fluoxetine and desipramine via separable substrates.
Leptin receptor deficiency confers resistance to behavioral effects of fluoxetine and desipramine via separable substrates.
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瘦素受体缺陷通过可分离的底物导致对氟西汀和地昔帕明行为效应的抵抗
DOI：
10.1038/tp.2014.126
复制
发表时间：
2014-12-02
影响因子：
6.8
通讯作者：
Lu XY
中科院分区：
文献类型：
--
作者：
Guo M;Lu XY
抑郁症是一种复杂的、异质性的精神障碍。目前可用的抗抑郁药只对大约三分之一到一半的患者有效。抗抑郁药物反应和治疗耐药性的机制尚不清楚。最近的临床证据表明瘦素参与抗抑郁药物的治疗反应。在这项研究中，我们确定了瘦素受体（LepRb）在选择性血清素能抗抑郁药氟西汀和去甲肾上腺素能抗抑郁药去西帕明的行为反应中的功能作用。在强迫游泳试验中，野生型小鼠用氟西汀或地西帕明进行急性和慢性治疗可产生抗抑郁样作用，而LepRb （db/db）无效的小鼠对氟西汀或地西帕明治疗均表现出耐药性。氟西汀刺激野生型小鼠海马和前额叶皮质（PFC）中Akt （Thr308）和GSK-3β (Ser9)的磷酸化，而db/db小鼠则没有。地西帕明未能诱导两种基因型小鼠海马、PFC以及下丘脑中Akt、GSK-3β或ERK1/2磷酸化发生可测量的变化。海马和皮质神经元特异性地缺失LepRb导致在强迫游泳试验和悬尾试验中氟西汀不敏感，而对地西帕明的反应保持不变。这些结果表明，功能性LepRb在调节氟西汀和地西帕明的抗抑郁样行为作用中起关键作用。氟西汀的抗抑郁作用依赖于海马体和皮质中功能性LepRb的存在，而非地西帕明。
Depression is a complex, heterogeneous mental disorder. Currently available antidepressants are only effective in about one-third to one-half of all patients. The mechanisms underlying antidepressant response and treatment resistance are poorly understood. Recent clinical evidence implicates the involvement of leptin in treatment response to antidepressants. In this study, we determined the functional role of the leptin receptor (LepRb) in behavioral responses to the selective serotonergic antidepressant fluoxetine and the noradrenergic antidepressant desipramine. While acute and chronic treatment with fluoxetine or desipramine in wild-type mice elicited antidepressant-like effects in the forced swim test, mice null for LepRb (db/db) displayed resistance to treatment with either fluoxetine or desipramine. Fluoxetine stimulated phosphorylation of Akt (Thr308) and GSK-3β (Ser9) in the hippocampus and prefrontal cortex (PFC) of wild-type mice but not in db/db mice. Desipramine failed to induce measurable changes in Akt, GSK-3β or ERK1/2 phosphorylation in the hippocampus and PFC, as well as hypothalamus of either genotype of mice. Deletion of LepRb specifically from hippocampal and cortical neurons resulted in fluoxetine insensitivity in the forced swim test and tail suspension test while leaving the response to desipramine intact. These results suggest that functional LepRb is critically involved in regulating the antidepressant-like behavioral effects of both fluoxetine and desipramine. The antidepressant effects of fluoxetine but not desipramine are dependent on the presence of functional LepRb in the hippocampus and cortex.
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DOI：
10.1136/bmj.b3765
发表时间：
2009-10-06
期刊：
BMJ (Clinical research ed.)
影响因子：
--
作者：
Kivimäki M;Lawlor DA;Singh-Manoux A;Batty GD;Ferrie JE;Shipley MJ;Nabi H;Sabia S;Marmot MG;Jokela M
通讯作者：
Jokela M
影响因子：
29
作者：
Lam DD;Leinninger GM;Louis GW;Garfield AS;Marston OJ;Leshan RL;Scheller EL;Christensen L;Donato J Jr;Xia J;Evans ML;Elias C;Dalley JW;Burdakov DI;Myers MG Jr;Heisler LK
通讯作者：
Heisler LK
DOI：
10.1017/s1461145712000703
发表时间：
2013-05
期刊：
The international journal of neuropsychopharmacology
影响因子：
--
作者：
Guo M;Huang TY;Garza JC;Chua SC;Lu XY
通讯作者：
Lu XY
影响因子：
6.9
作者：
Chen, G;Manji, HK
通讯作者：
Manji, HK
前脑谷氨酸能神经元介导瘦素对抑郁样行为和突触抑郁症的作用。
影响因子：
6.8
作者：
Guo M;Lu Y;Garza JC;Li Y;Chua SC;Zhang W;Lu B;Lu XY
通讯作者：
Lu XY