Departament of Experimental Neuropharmacology, Instituto de Investigaciones Biológicas Clemente Estable, Uruguay.
Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
Behav Brain Res. 2019 Nov 18;374:112120. doi: 10.1016/j.bbr.2019.112120. Epub 2019 Jul 31.
Animal studies have shown that antagonists of receptor 1 of Melanin-Concentrating Hormone (MCH-R1) elicit antidepressive-like behavior, suggesting that MCH-R1 might be a novel target for the treatment of depression and supports the hypothesis that MCHergic signaling regulates depressive-like behaviors. Consistent with the evidence that MCHergic neurons send projections to dorsal and median raphe nuclei, we have previously demonstrated that MCH microinjections in both nuclei induced a depressive-like behavior. Even though MCH neurons also project to Locus Coeruleus (LC), only a few studies have reported the behavioral and neurochemical effect of MCH into the LC. We studied the effects of MCH (100 and 200 ng) into the LC on coping-stress related behaviors associated with depression, using two different behavioral tests: the forced swimming test (FST) and the learned helplessness (LH). To characterize the functional interaction between MCH and the noradrenergic LC system, we also evaluated the neurochemical effects of MCH (100 ng) on the extracellular levels of noradrenaline (NA) in the medial prefrontal cortex (mPFC), an important LC terminal region involved in emotional processing. MCH administration into the LC elicited a depressive-like behavior evidenced in both paradigms. Interestingly, in the LH, MCH (100) elicited a significant increase in escape failures only in stressed animals. A significant decrease in prefrontal levels of NA was observed after MCH microinjection into the LC. Our results demonstrate that increased MCH signaling into the LC triggers depressive-like behaviors, especially in stressed animals. These data further corroborate the important role of MCH in the neurobiology of depression.
动物研究表明，黑色素聚集激素受体 1（MCH-R1）的拮抗剂会引发抗抑郁样行为，这表明 MCH-R1 可能是治疗抑郁症的新靶点，并支持了 MCH 能信号调节抑郁样行为的假说。与 MCH 能神经元向背侧和中缝核投射的证据一致，我们之前已经证明，在这两个核内微注射 MCH 会引起抗抑郁样行为。尽管 MCH 神经元也向蓝斑投射，但只有少数研究报告了 MCH 进入蓝斑对行为和神经化学的影响。我们研究了 MCH（100 和 200ng）进入蓝斑对与抑郁相关的应对压力相关行为的影响，使用了两种不同的行为测试：强迫游泳测试（FST）和习得性无助（LH）。为了描述 MCH 与去甲肾上腺素能蓝斑系统之间的功能相互作用，我们还评估了 MCH（100ng）对内侧前额叶皮质（mPFC）中去甲肾上腺素（NA）的细胞外水平的神经化学影响，mPFC 是一个涉及情绪处理的重要 LC 末梢区域。MCH 进入蓝斑会引起两种模型中的抗抑郁样行为。有趣的是，在 LH 中，MCH（100）仅在应激动物中引起明显的逃避失败增加。MCH 进入蓝斑微注射后，前额叶的 NA 水平显著下降。我们的结果表明，增加进入蓝斑的 MCH 信号会引发抗抑郁样行为，尤其是在应激动物中。这些数据进一步证实了 MCH 在抑郁症神经生物学中的重要作用。
