A Study of the Involvement of Melanin-Concentrating Hormone Receptor 1 (MCHR1) in Murine Models of Depression

Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
Biological Psychiatry (Impact Factor: 10.26). 02/2007; 61(2):174-80. DOI: 10.1016/j.biopsych.2006.03.076
Source: PubMed


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.

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    • "In addition, following a 5-week exposure to repeated chronic mild stress (an ethologically relevant animal model of depression), in C57Bl/6J mice there is an increase in the hippocampal gene expression of MCHR-1. This increased gene expression was reversed by chronic fluoxetine treatment (Roy et al., 2007). The importance of the MCHergic system in MD is emphasized in a recent study which suggests that an increase in the expression of preproMCH and consequent MCH receptor down-regulation could be a biomarker of the severity of depressive disorders (García-Fuster et al., 2012). "
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    ABSTRACT: The melanin-concentrating hormone (MCH) is a peptidergic neuromodulator synthesized by neurons of the lateral sector of the posterior hypothalamus and zona incerta. MCHergic neurons project throughout the central nervous system, including areas such as the dorsal (DR) and median (MR) raphe nuclei, which are involved in the control of sleep and mood. Major Depression (MD) is a prevalent psychiatric disease diagnosed on the basis of symptomatic criteria such as sadness or melancholia, guilt, irritability, and anhedonia. A short REM sleep latency (i.e., the interval between sleep onset and the first REM sleep period), as well as an increase in the duration of REM sleep and the density of rapid-eye movements during this state, are considered important biological markers of depression. The fact that the greatest firing rate of MCHergic neurons occurs during REM sleep and that optogenetic stimulation of these neurons induces sleep, tends to indicate that MCH plays a critical role in the generation and maintenance of sleep, especially REM sleep. In addition, the acute microinjection of MCH into the DR promotes REM sleep, while immunoneutralization of this peptide within the DR decreases the time spent in this state. Moreover, microinjections of MCH into either the DR or MR promote a depressive-like behavior. In the DR, this effect is prevented by the systemic administration of antidepressant drugs (either fluoxetine or nortriptyline) and blocked by the intra-DR microinjection of a specific MCH receptor antagonist. Using electrophysiological and microdialysis techniques we demonstrated also that MCH decreases the activity of serotonergic DR neurons. Therefore, there are substantive experimental data suggesting that the MCHergic system plays a role in the control of REM sleep and, in addition, in the pathophysiology of depression. Consequently, in the present report, we summarize and evaluate the current data and hypotheses related to the role of MCH in REM sleep and MD.
    Full-text · Article · Dec 2015 · Frontiers in Neuroscience
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    • "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. "
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    ABSTRACT: In preclinical studies, the hypothalamic polypeptide melanin-concentrating hormone (MCH) has been shown to be involved in depression-like behavior and modulations of MCH and MCH-receptors were proposed as potential new antidepressant drug targets. For the first time, MCH serum levels were explored in 30 patients with major depressive disorder (MDD) prior to (T1) and after 2 (T2) and 4 weeks (T3) of antidepressant treatment and in 30 age- and sex-matched healthy controls by applying a fluorescence immunoassay. Levels of MCH did not differ significantly between un-medicated patients (444.11±174.63pg/mL SD) and controls (450.68±210.03pg/mL SD). In MDD patients, MCH levels significantly decreased from T1 to T3 (F=4.663; p=0.013). Post-hoc analyses showed that these changes were limited to patients treated with mirtazapine but not escitalopram and female but not male patients. MCH-levels showed high correlations from T1 to T3 (r≥0.964, p<0.001) and were found to correlate significantly with parameters of sleep within the controls. Small sample size. No follow-up measures were performed within the control group. Our findings suggest peripheral MCH-levels not to be altered in depression but possibly reflecting depression-related state properties that can be modulated by sleep, medication and sex. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Apr 2015 · Journal of Affective Disorders
    • "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). "
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    ABSTRACT: Melanin-concentrating Hormone (MCH) is a 19 amino acid cyclic neuropeptide that acts in rodents via the MCH receptor 1 (MCHR1) to regulate a wide variety of physiological functions. MCH is produced by a distinct population of neurons located in the lateral hypothalamus (LH) and zona incerta (ZI) but MCHR1 mRNA is widely expressed throughout the brain. The physiological responses and behaviors regulated by the MCH system have been investigated, but less is known about how MCH neurons are regulated. The effects of most classical neurotransmitters on MCH neurons have been studied, but those of neuropeptides are poorly understood. In order to gain insight into how neuropeptides regulate the MCH system, we investigated which neuropeptide receptors are expressed by MCH neurons using double in situ hybridization. In all, twenty receptors, selected based upon either a suspected interaction with the MCH system or demonstrated high expression levels in the LH and ZI, were tested to determine whether they are expressed by MCH neurons. Overall, eleven neuropeptide receptors were found to exhibit significant colocalization with MCH neurons: Nociceptin / Orphanin FQ Opioid receptor (NOP), MCHR1, both Orexin receptors (ORX), Somatostatin receptor 1 and 2 (SSTR1, SSTR2), the Kisspeptin receotor (KissR1), Neurotensin receptor 1 (NTSR1), Neuropeptide S receptor (NPSR), Cholecystokinin receptor A (CCKAR) and the κ-opioid receptor (KOR). Of these receptors, six have never before been linked to the MCH system. Surprisingly, several receptors thought to regulate MCH neurons displayed minimal colocalization with MCH, suggesting that they may not directly regulate the MCH system. J. Comp. Neurol., 2014. © 2014 Wiley Periodicals, Inc.
    No preview · Article · Dec 2014 · The Journal of Comparative Neurology
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