Most antidepressant medications target central monoamine systems and are often characterized by limited efficacies and unwanted side effects. Thus, significant efforts are ongoing to identify novel targets for the treatment of depression. Growing evidence suggests that neuropeptides play a role in the pathophysiology of depression. The melanin-concentrating hormone (MCH) is one such neuropeptide, implicated in the modulation of many physiological responses.
We utilized an array of techniques including chronic mild stress (CMS) as a depression paradigm, neurobehavior, gene expression analysis, and knockout genetics to investigate the role of MCH receptor subtype 1 (MCHR1) in murine models of depression.
We report here that following a 5-week exposure to repeated chronic mild stress (an ethologically relevant animal model of depression), C57Bl/6J mice have increased hippocampal gene expression of MCH receptor subtype 1 (MCHR1), the cognate melanin concentrating hormone receptor in mice. This increased gene expression is reversed by chronic fluoxetine hydrochloride (Prozac) treatment. Additionally, while female and male mice carrying a null mutation of the MCHR1 gene show comparable anxiolytic-like behavior on the open field, only female knockout mice exhibit antidepressant-like behavior, when tested on the forced swim and tail suspension tests.
Taken together, we suggest that antagonism of the MCHR1 receptor may provide a novel approach for the treatment of affective disorders, including depression, with a potentially increased efficacy in women.
"A body of preclinical findings points towards an impact of MCH-activity on depression-like behavior and suggests possible treatment options via alteration of MCH (Chung et al., 2011). Most investigations on animals report a depressiogenic effect of MCH whereas antagonizing MCH-action by receptor-modulation could lead to reduced depressive behavior (Georgescu et al., 2005; Lagos et al., 2011; Borowsky et al., 2002; Roy et al., 2007). Our results of missing group differences do not indicate a hyper-or hyposecretion of MCH within untreated depressed subjects. "
"It was discovered that MCHR1 antagonists also exert anxiolytic and antidepressant effects (Borowsky et al., 2002), which led to the investigation of other physiological functions of the MCH system. In recent years, MCH has been implicated in the regulation of metabolism, reward, anxiety and depression-like behaviors, sleep, learning and memory, and seizure threshold, among other functions (Chaki et al., 2005; Chung et al., 2009; Garcia-Fuster et al., 2012; Lagos et al., 2009; Lee et al., 2011; Parks et al., 2010; Qu et al., 1996; Roy et al., 2007; Shimada et al., 1998; Verret et al., 2003). MCH is regarded as an inhibitory peptide, because MCHR1 couples to G i /G o and typically inhibits the activity of postsynaptic target neurons (Gao and van den Pol, 2001, 2002). "
"There have been contradictory reports about the anxiety-related behavior of MCH signaling-deficient mice , , , , . Our meta-analysis did not produce clear conclusions regarding the effects of MCH signaling deficiency on anxiety; weak anxiolytic effects were found for in the elevated plus maze and open field tests, but weak anxiogenic effects were found in the emergence test. "
[Show abstract][Hide abstract] ABSTRACT: The demand for meta-analyses in basic biomedical research has been increasing because the phenotyping of genetically modified mice does not always produce consistent results. Melanin-concentrating hormone (MCH) has been reported to be involved in a variety of behaviors that include feeding, body-weight regulation, anxiety, sleep, and reward behavior. However, the reported behavioral and metabolic characteristics of MCH signaling-deficient mice, such as MCH-deficient mice and MCH receptor 1 (MCHR1)-deficient mice, are not consistent with each other. In the present study, we performed a meta-analysis of the published data related to MCH-deficient and MCHR1-deficient mice to obtain robust conclusions about the role of MCH signaling. Overall, the meta-analysis revealed that the deletion of MCH signaling enhanced wakefulness, locomotor activity, aggression, and male sexual behavior and that MCH signaling deficiency suppressed non-REM sleep, anxiety, responses to novelty, startle responses, and conditioned place preferences. In contrast to the acute orexigenic effect of MCH, MCH signaling deficiency significantly increased food intake. Overall, the meta-analysis also revealed that the deletion of MCH signaling suppressed the body weight, fat mass, and plasma leptin, while MCH signaling deficiency increased the body temperature, oxygen consumption, heart rate, and mean arterial pressure. The lean phenotype of the MCH signaling-deficient mice was also confirmed in separate meta-analyses that were specific to sex and background strain (i.e., C57BL/6 and 129Sv). MCH signaling deficiency caused a weak anxiolytic effect as assessed with the elevated plus maze and the open field test but also caused a weak anxiogenic effect as assessed with the emergence test. MCH signaling-deficient mice also exhibited increased plasma corticosterone under non-stressed conditions, which suggests enhanced activity of the hypothalamic-pituitary-adrenal axis. To the best of our knowledge, the present work is the first study to systematically compare the effects of MCH signaling on behavioral and metabolic phenotypes.
PLoS ONE 06/2014; 9(6):e99961. DOI:10.1371/journal.pone.0099961 · 3.23 Impact Factor
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