Administration Of Melanin-concentrating Hormone Research Articles

Angiostrongylus cantonensis induces energy imbalance and dyskinesia in mice by reducing the expression of melanin-concentrating hormone

BackgroundInfection with Angiostrongylus cantonensis (AC) in humans or mice can lead to severe eosinophilic meningitis or encephalitis, resulting in various neurological impairments. Developing effective neuroprotective drugs to improve the quality of life in affected individuals is critical.MethodsWe conducted a Gene Ontology enrichment analysis on microarray gene expression (GSE159486) in the brains of AC-infected mice. The expression levels of melanin-concentrating hormone (MCH) were confirmed through real-time quantitative PCR (RT–qPCR) and immunofluorescence. Metabolic parameters were assessed using indirect calorimetry, and mice’s energy metabolism was evaluated via pathological hematoxylin and eosin (H&E) staining, serum biochemical assays, and immunohistochemistry. Behavioral tests assessed cognitive and motor functions. Western blotting was used to measure the expression of synapse-related proteins. Mice were supplemented with MCH via nasal administration.ResultsPostinfection, a marked decrease in Pmch expression and the encoded MCH was observed. Infected mice exhibited significant weight loss, extensive consumption of sugar and white fat tissue, reduced movement distance, and decreased speed, compared with the control group. Notably, nasal administration of MCH countered the energy imbalance and dyskinesia caused by AC infection, enhancing survival rates. MCH treatment also increased the expression level of postsynaptic density protein 95 (PSD95) and microtubule-associated protein-2 (MAP2), as well as upregulated transcription level of B cell leukemia/lymphoma 2 (Bcl2) in the cortex.ConclusionsOur findings suggest that MCH improves dyskinesia by reducing loss of synaptic proteins, indicating its potential as a therapeutic agent for AC infection.Graphical

Taisho-Sanshoku koi have hardly faded skin and show attenuated melanophore sensitivity to adrenaline and melanin-concentrating hormone.

Koi carp, an ornamental fish derived from the common carp Cyprinus carpio (CC), is characterized by beautiful skin color patterns. However, the mechanism that gives rise to the characteristic vivid skin coloration of koi carp has not been clarified. The skin coloration of many teleosts changes in response to differences in the background color. This change in skin coloration is caused by diffusion or aggregation of pigment granules in chromatophores and is regulated mainly by sympathetic nerves and hormones. We hypothesized that there would be some abnormality in the mechanism of skin color regulation in koi carp, which impairs skin color fading in response to background color. We compared the function of melanin-concentrating hormone (MCH), noradrenaline, and adrenaline in CC and Taisho-Sanshoku (TS), a variety of tri-colored koi. In CC acclimated to a white background, the skin color became paler and pigment granules aggregated in melanophores in the scales compared to that in black-acclimated CC. There were no clear differences in skin color or pigment granule aggregation in white- or black-acclimated TS. The expression of mch1 mRNA in the brain was higher in the white-acclimated CC than that in the black-acclimated CC. However, the expression of mch1 mRNA in the brain in the TS did not change in response to the background color. Additionally, plasma MCH levels did not differ between white- and black-acclimated fish in either CC or TS. In vitro experiments showed that noradrenaline induced pigment aggregation in scale melanophores in both CC and TS, whereas adrenaline induced pigment aggregation in the CC but not in the TS. In vitro administration of MCH induced pigment granule aggregation in the CC but not in the TS. However, intraperitoneal injection of MCH resulted in pigment granule aggregation in both CC and TS. Collectively, these results suggest that the weak sensitivity of scale melanophores to MCH and adrenaline might be responsible for the lack of skin color change in response to background color in the TS.

Melanin-concentrating hormone interferes with the hypothalamic-pituitary-gonad axis in the Mozambique tilapia

This study was conducted to elucidate the influence of melanin-concentrating hormone (MCH) along the reproductive-axis in the female tilapia Oreochromis mossambicus. Administration of MCH (4 μg / 0.1 ml saline) for 22 days resulted in significantly lower gonadosomatic index compared to controls. Significant reduction in the mean numbers of follicles at different stages of development such as previtellogenic (stages I-III), vitellogenic (stage IV) and preovulatory (stage V) follicles was observed in MCH-treated fish compared with controls. On the other hand, the rate of atresia was significantly higher in follicles at stages II, III and IV in MCH-treated fish. In addition, in the pituitary gland, sparsely labelled gonadotropin releasing hormone (GnRH)-immunoreactive fibres were observed in MCH-treated fish in contrast to their intense labelling in controls. The serum level of luteinizing hormone (LH) showed significant decrease, but the serum cortisol level rose significantly following MCH treatment compared to those of controls. Collectively, these results indicate for the first time, that MCH treatment blocks follicular development during the ovarian cycle, possibly through the suppression of GnRH-LH axis in fish. The results also indicate that MCH may activate the stress-axis pathway in fish.

Restored TDCA and valine levels imitate the effects of bariatric surgery.

Obesity is widespread and linked to various co-morbidities. Bariatric surgery has been identified as the only effective treatment, promoting sustained weight loss and the remission of co-morbidities. Metabolic profiling was performed on diet-induced obese (DIO) mice, lean mice, and DIO mice that underwent sleeve gastrectomies (SGx). In addition, mice were subjected to intraperitoneal (i.p.) injections with taurodeoxycholic acid (TDCA) and valine. Indirect calorimetry was performed to assess food intake and energy expenditure. Expression of appetite-regulating hormones was assessed through quantification of isolated RNA from dissected hypothalamus tissue. Subsequently, i.p. injections with a melanin-concentrating hormone (MCH) antagonist and intrathecal administration of MCH were performed and weight loss was monitored. Mass spectrometric metabolomic profiling revealed significantly reduced systemic levels of TDCA and L-valine in DIO mice. TDCA and L-valine levels were restored after SGx in both human and mice to levels comparable with lean controls. Systemic treatment with TDCA and valine induced a profound weight loss analogous to effects observed after SGx. Utilizing indirect calorimetry, we confirmed reduced food intake as causal for TDCA/valine-mediated weight loss via a central inhibition of the MCH. In summary, we identified restored TDCA/valine levels as an underlying mechanism of SGx-derived effects on weight loss. Of translational relevance, TDCA and L-valine are presented as novel agents promoting weight loss while reversing obesity-associated metabolic disorders. This work has been supported in part by a grant from NIH (UO-1 A1 132898 to S.G.T., DP and MA). M.Q. was supported by the IFB Integrated Research and Treatment Centre Adiposity Diseases (Leipzig, Germany) and the German Research Foundation (QU 420/1-1). J.I. was supported by the Biomedical Education Program (BMEP) of the German Academic Exchange Service (DAAD). T.H. (HE 7457/1-1) and F.K. (KR 4362/1-1) were supported by the German Research Foundation (DFG). H.R.C.B. was supported the Swiss Society of Cardiac Surgery. Y.N. was supported by the Chinese Scholarship Council (201606370196) and Central South University. H.U., T.M. and R.M. were supported by the Osaka Medical Foundation. C.S.F. was supported by the German Research Foundation (DFG, SFB738, B3).

Intranasal Administration of Melanin-Concentrating Hormone Reduces Stress-Induced Anxiety- and Depressive-Like Behaviors in Rodents.

Major depressive disorder is a complex neuropsychiatric disorder with few treatment options. Non-targeted antidepressants have low efficacy and can induce series of side effects. While a neuropeptide, melanin-concentrating hormone (MCH), is known to exhibit regulator of affective state, no study to date has assessed the anti-depressive effects of MCH in a stress-induced depression model. This study aimed to evaluate the pharmacological effects of intranasal administration of MCH on depression-related behavior in stressed rats and mice. Using a number of behavioral tests, we found that MCH treatment significantly decreased anxiety- and depressive-like behaviors induced by stress. Notably, the effects of MCH were equivalent to those of fluoxetine. MCH treatment also restored the activity of the mammalian target of rapamycin (mTOR) signaling pathway and normalized the levels of synaptic proteins, including postsynaptic density 95, glutamate receptor 1, and synapsin 1, which were all downregulated by stress. Interestingly, the protective effects of MCH were blocked by the mTOR inhibitor, rapamycin. These results suggest that MCH exhibits antidepressant properties by modulating the mTOR pathway. Altogether, this study provides an insight into the molecular mechanisms involved in the antidepressant-like effects of MCH, thereby paving the way for the future clinical application of MCH.

Melanin-concentrating hormone (MCH) in the median raphe nucleus: Fibers, receptors and cellular effects

Serotonergic neurons of the median raphe nucleus (MnR) and hypothalamic melanin-concentrating hormone (MCH)-containing neurons, have been involved in the control of REM sleep and mood.In the present study, we examined in rats and cats the anatomical relationship between MCH-containing fibers and MnR neurons, as well as the presence of MCHergic receptors in these neurons. In addition, by means of in vivo unit recording in urethane anesthetized rats, we determined the effects of MCH in MnR neuronal firing.Our results showed that MCH-containing fibers were present in the central and paracentral regions of the MnR. MCHergic fibers were in close apposition to serotonergic and non-serotonergic neurons. By means of an indirect approach, we also analyzed the presence of MCHergic receptors within the MnR. Accordingly, we microinjected MCH conjugated with the fluorophore rhodamine (R-MCH) into the lateral ventricle. R-MCH was internalized into serotonergic and non-serotonergic MnR neurons; some of these neurons were GABAergic. Furthermore, we determined that intracerebroventricular administration of MCH induced a significant decrease in the firing rate of 53 % of MnR neurons, while the juxtacellular administration of MCH reduced the frequency of discharge in 67 % of these neurons. Finally, the juxtacellular administration of the MCH-receptor antagonist ATC-0175 produced an increase in the firing rate in 78 % of MnR neurons. Hence, MCH produces a strong regulation of MnR neuronal activity. We hypothesize that MCHergic modulation of the MnR neuronal activity may be involved in the promotion of REM sleep and in the pathophysiology of depressive disorders.

Intranasal administration of melanin-concentrating hormone modulates stress response by mTOR signaling pathway

Intranasal administration of melanin-concentrating hormone modulates stress response by mTOR signaling pathway

Melanin-concentrating hormone receptor-1 is located in primary cilia of the dorsal raphe neurons

The melanin-concentrating hormone (MCH) is a peptidergic neuromodulator synthesized by neurons of the posterior hypothalamus and incerto-hypothalamic area. These neurons project throughout the central nervous system, including the dorsal raphe nucleus (DRN). In rodents, MCH exerts its biological functions through the MCHR-1 receptor. We previously demonstrated that intra-DRN MCH administration increases REM sleep time and induces a pro-depressive behavior. We also determined that MCH modulates the neuronal firing rate and serotonin release within this nucleus. Previous studies in mice identified the presence of MCHR-1 in neurons located in the olfactory tubercle, hypothalamus, and nucleus accumbens, in a specialized neuronal appendage: the neuronal primary cilia. However, the subcellular location of MCHR-1 protein in the DRN is still unknown. Hence, the aim of the present study was to explore, by means of single and double immunohistochemical procedures, whether MCHR-1 is present in neuronal primary cilia in serotonergic and GABAergic neurons located in the DRN of the rat. We demonstrated colocalization of MCHR-1 with type III adenylyl cyclase (AC-III), a neuronal ciliary marker, in the DRN and confirmed their colocalization in the hippocampus and cerebral cortex of the rat. We quantified the proportion of serotoninergic and GABAergic neurons that coexpress MCHR-1 at the mid-caudal and mid-rostral levels of the DRN: 4% and 12%, respectively. Furthermore, approximately 10% of the total number of MCHR-1 immunoreactive primary cilia belonged to serotonergic neurons, whilst 12% were appendages of GABAergic neurons. These morphological data allow us to conclude that the mechanism by which MCH modulates the activity of DRN neurons is through MCHR-1 receptors present in the primary cilia of different neurochemical phenotypes. New experiments are needed to understand the functional rationale of the unexpected localization of these receptors and to explore their presence in other neuronal phenotypes.

Melanin-concentrating hormone does not modulate serotonin release in primary cultures of fetal raphe nucleus neurons

Melanin-concentrating hormone (MCH) is a neuropeptide present in neurons located in the hypothalamus that densely innervate serotonergic cells in the dorsal raphe nucleus (DRN). MCH administration into the DRN induces a depressive-like effect through a serotonergic mechanism. To further understand the interaction between MCH and serotonin, we used primary cultured serotonergic neurons to evaluate the effect of MCH on serotonergic release and metabolism by HPLC-ED measurement of serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) levels. We confirmed the presence of serotonergic neurons in the E14 rat rhombencephalon by immunohistochemistry and showed for the first time evidence of MCHergic fibers reaching the area. Cultures obtained from rhombencephalic tissue presented 2.2 ± 0.7% of serotonergic and 48.9 ± 5.4% of GABAergic neurons. Despite the low concentration of serotonergic neurons, we were able to measure basal cellular and extracellular levels of 5-HT and 5-HIAA without the addition of any serotonergic-enhancer drug. As expected, 5-HT release was calcium-dependent and induced by depolarization. 5-HT extracellular levels were significantly increased by incubation with serotonin reuptake inhibitors (citalopram and nortriptyline) and a monoamine-oxidase inhibitor (clorgyline), and were not significantly modified by a 5-HT1A autoreceptor agonist (8-OHDPAT). Even though serotonergic cells responded as expected to these pharmacological treatments, MCH did not induce significant modifications of 5-HT and 5-HIAA extracellular levels in the cultures. Despite this unexpected result, we consider that assessment of 5-HT and 5-HIAA levels in primary serotonergic cultures may be an adequate approach to study the effect of other drugs and modulators on serotonin release, uptake and turnover.

Subchronical treatment with Fluoxetine modifies the activity of the MCHergic and hypocretinergic systems. Evidences from peptide CSF concentration and gene expression

In the postero-lateral hypothalamus are located two neuronal systems that utilize the neuropeptides melanin-concentrating hormone (MCH) and hypocretins (also called orexins) as neuromodulators. These systems have reciprocal connections between them, and project throughout the central nervous system. MCH has been involved in the generation of sleep, mainly REM sleep, while hypocretins have a critical role in the generation of wakefulness.MCHergic activity is also involved in the pathophysiology of major depressive disorder (MD). In this regards, intracerebral administration of MCH promotes pro-depressive behaviors (i.e., immobility in the forced swimming test) and REM sleep hypersomnia, which is an important trait of depression. Furthermore, the antagonism of the MCHR-1 receptor has a reliable antidepressant effect, suggesting that MCH is a pro-depressive factor. Hypocretins have been also involved in mood regulation; however, their role in depression is still on debate.Taking these data into account, we explored whether systemic subchronical treatment with Fluoxetine (FLX), a serotonergic antidepressant, modifies the concentration of MCH in the cerebrospinal fluid (CSF), as well as the preproMCH mRNA expression. We also evaluated the hypocretinergic system by quantifying the hypocretin-levels in the CSF and the preprohypocretin mRNA expression.Compared to control, FLX increased the levels of preprohypocretin mRNA without affecting the hypocretin-1 CSF levels. On the contrary, FLX significantly decreased the MCH CSF concentration without affecting the preproMCH gene expression. This result is in agreement with the fact that MCH serum level diminishes during the antidepressant treatment in MD, and supports the hypothesis that an increase in the MCHergic activity could have pro-depressive consequences.

Melanin-concentrating hormone (MCH) modulates the activity of dorsal raphe neurons

Hypothalamic neurons that utilize melanin-concentrating hormone (MCH) as a neuromodulator are localized in the postero-lateral hypothalamus and incerto-hypothalamic area. These neurons send dense projections to the dorsal raphe nucleus (DRN).Serotonergic neurons of the DRN are involved in the control of sleep and play a critical role in major depression. Previously, we demonstrated that microinjections of MCH into the DRN resulted in an increase in REM sleep and produce a depressive-like effect. In the present study we examined the mechanisms that mediate these effects by employing neuroanatomical and electrophysiological techniques.First, we determined that rhodamine-labeled MCH (R-MCH), when microinjected into the lateral ventricle, is internalized in serotonergic and non-serotonergic DRN neurons in rats and cats. These data strongly suggest that these neurons express MCHergic receptors. Second, in rats, we demonstrated that the microinjection of MCH into the lateral ventricle results in a significant decrease in the firing rate in 59% of the neurons recorded in the DRN; the juxtacellular administration of MCH reduced the discharge in 80% of these neurons. Some of the neurons affected by MCH were likely serotonergic on the basis of their electrophysiological and pharmacological properties.We conclude that MCH reduces the activity of serotonergic neurons of the DRN. These and previous data suggest that the MCHergic modulation of serotonergic activity within the DRN is involved in the regulation of REM sleep as well as in the pathophysiology of depressive disorders.

Prodepressive effect induced by microinjections of MCH into the dorsal raphe: time course, dose dependence, effects on anxiety-related behaviors, and reversion by nortriptyline.

Melanin-concentrating hormone (MCH) administered within the rat dorsal raphe nucleus (DRN) has been shown to elicit prodepressive behaviors in the forced-swim test. The present study was designed to evaluate the time course (30 and 60 min) and dose dependence (25-100 ng) of this effect, and whether it would be antagonized by an intra-DRN microinjection of the MCH-1 receptor antagonist ATC0175 (ATC, 1 mmol/l) or intraperitoneal pretreatment with the noradrenergic antidepressant nortriptyline (20 mg/kg). The results showed that the behavioral effect of MCH was time and dose dependent as immobility was increased, and climbing decreased, only by the 50 ng MCH dose at T30. The effect was mediated by MCH-1 receptors as a significant blockade of this behavioral response was observed in ATC-pretreated animals. ATC did not by itself modify animal behavior. Nortriptyline also prevented the prodepressive-like effect of MCH. Concomitantly, the effect of MCH (50 ng) at T30 on anxiety-related behaviors was assessed using the elevated plus-maze. Interestingly, these behaviors were unchanged. In conclusion, MCH administration within the DRN elicits, through the MCH-1 receptor, a depression-related behavior that is not accompanied by changes in anxiety and that is prevented by a noradrenergic antidepressant.

Central Melanin-Concentrating Hormone Influences Liver and Adipose Metabolism Via Specific Hypothalamic Nuclei and Efferent Autonomic/JNK1 Pathways

Specific neuronal circuits modulate autonomic outflow to liver and white adipose tissue. Melanin-concentrating hormone (MCH)-deficient mice are hypophagic, lean, and do not develop hepatosteatosis when fed a high-fat diet. Herein, we sought to investigate the role of MCH, an orexigenic neuropeptide specifically expressed in the lateral hypothalamic area, on hepatic and adipocyte metabolism. Chronic central administration of MCH and adenoviral vectors increasing MCH signaling were performed in rats and mice. Vagal denervation was performed to assess its effect on liver metabolism. The peripheral effects on lipid metabolism were assessed by real-time polymerase chain reaction and Western blot. We showed that the activation of MCH receptors promotes nonalcoholic fatty liver disease through the parasympathetic nervous system, whereas it increases fat deposition in white adipose tissue via the suppression of sympathetic traffic. These metabolic actions are independent of parallel changes in food intake and energy expenditure. In the liver, MCH triggers lipid accumulation and lipid uptake, with c-Jun N-terminal kinase being an essential player, whereas in adipocytes MCH induces metabolic pathways that promote lipid storage and decreases lipid mobilization. Genetic activation of MCH receptors or infusion of MCH specifically in the lateral hypothalamic area modulated hepatic lipid metabolism, whereas the specific activation of this receptor in the arcuate nucleus affected adipocyte metabolism. Our findings show that central MCH directly controls hepatic and adipocyte metabolism through different pathways.

Microinjection of melanin concentrating hormone into the lateral preoptic area promotes non-REM sleep in the rat

The ventrolateral preoptic area (VLPO) has been recognized as one of the key structures responsible for the generation of non-REM (NREM) sleep. The melanin-concentrating hormone (MCH)-containing neurons, which are located in the lateral hypothalamus and incerto-hypothalamic area, project widely throughout the central nervous system and include projections to the VLPO. The MCH has been associated with the central regulation of feeding and energy homeostasis. In addition, recent findings strongly suggest that the MCHergic system promotes sleep. The aim of the present study was to determine if MCH generates sleep by regulating VLPO neuronal activity. To this purpose, we characterized the effect of unilateral and bilateral microinjections of MCH into the VLPO on sleep and wakefulness in the rat. Unilateral administration of MCH into the VLPO and adjacent dorsal preoptic area did not modify sleep. On the contrary, bilateral microinjections of MCH (100ng) into these areas significantly increased light sleep (LS, 39.2±4.8 vs. 21.6±2.5min, P<0.05) and total NREM sleep (142.4±23.2 vs. 86.5±10.5min, P<0.05) compared to control (saline) microinjections. No effect was observed on REM sleep. We conclude that MCH administration into the VLPO and adjacent dorsal lateral preoptic area promotes the generation of NREM sleep.

The Melanin-Concentrating Hormone (MCH) System Modulates Behaviors Associated with Psychiatric Disorders

Deficits in sensorimotor gating measured by prepulse inhibition (PPI) of the startle have been known as characteristics of patients with schizophrenia and related neuropsychiatric disorders. PPI disruption is thought to rely on the activity of the mesocorticolimbic dopaminergic system and is inhibited by most antipsychotic drugs. These drugs however act also at the nigrostriatal dopaminergic pathway and exert adverse locomotor responses. Finding a way to inhibit the mesocorticolimbic- without affecting the nigrostriatal-dopaminergic pathway may thus be beneficial to antipsychotic therapies. The melanin-concentrating hormone (MCH) system has been shown to modulate dopamine-related responses. Its receptor (MCH1R) is expressed at high levels in the mesocorticolimbic and not in the nigrostriatal dopaminergic pathways. Interestingly a genomic linkage study revealed significant associations between schizophrenia and markers located in the MCH1R gene locus. We hypothesize that the MCH system can selectively modulate the behavior associated with the mesocorticolimbic dopamine pathway. Using mice, we found that central administration of MCH potentiates apomorphine-induced PPI deficits. Using congenic rat lines that differ in their responses to PPI, we found that the rats that are susceptible to apomorphine (APO-SUS rats) and exhibit PPI deficits display higher MCH mRNA expression in the lateral hypothalamic region and that blocking the MCH system reverses their PPI deficits. On the other hand, in mice and rats, activation or inactivation of the MCH system does not affect stereotyped behaviors, dopamine-related responses that depend on the activity of the nigrostriatal pathway. Furthermore MCH does not affect dizocilpine-induced PPI deficit, a glutamate related response. Thus, our data present the MCH system as a regulator of sensorimotor gating, and provide a new rationale to understand the etiologies of schizophrenia and related psychiatric disorders.

Melanin concentrating hormone (MCH) gene expression changes in conditioned taste aversion (CTA), however MCH administration does not block CTA

Melanin concentrating hormone (MCH) gene expression changes in conditioned taste aversion (CTA), however MCH administration does not block CTA

Chronic Loss of Melanin-Concentrating Hormone Affects Motivational Aspects of Feeding in the Rat

Current epidemic obesity levels apply great medical and financial pressure to the strenuous economy of obesity-prone cultures, and neuropeptides involved in body weight regulation are regarded as attractive targets for a possible treatment of obesity in humans. The lateral hypothalamus and the nucleus accumbens shell (AcbSh) form a hypothalamic-limbic neuropeptide feeding circuit mediated by Melanin-Concentrating Hormone (MCH). MCH promotes feeding behavior via MCH receptor-1 (MCH1R) in the AcbSh, although this relationship has not been fully characterized. Given the AcbSh mediates reinforcing properties of food, we hypothesized that MCH modulates motivational aspects of feeding.Here we show that chronic loss of the rat MCH-precursor Pmch decreased food intake predominantly via a reduction in meal size during rat development and reduced high-fat food-reinforced operant responding in adult rats. Moreover, acute AcbSh administration of Neuropeptide-GE and Neuropeptide-EI (NEI), both additional neuropeptides derived from Pmch, or chronic intracerebroventricular infusion of NEI, did not affect feeding behavior in adult pmch +/+ or pmch −/− rats. However, acute administration of MCH to the AcbSh of adult pmch −/− rats elevated feeding behavior towards wild type levels. Finally, adult pmch −/− rats showed increased ex vivo electrically evoked dopamine release and increased limbic dopamine transporter levels, indicating that chronic loss of Pmch in the rat affects the limbic dopamine system.Our findings support the MCH-MCH1R system as an amplifier of consummatory behavior, confirming this system as a possible target for the treatment of obesity. We propose that MCH-mediated signaling in the AcbSh positively mediates motivational aspects of feeding behavior. Thereby it provides a crucial signal by which hypothalamic neural circuits control energy balance and guide limbic brain areas to enhance motivational or incentive-related aspects of food consumption.

Depressive-like profile induced by MCH microinjections into the dorsal raphe nucleus evaluated in the forced swim test

Antagonism of the melanin-concentrating hormone (MCH) receptor 1 (MCH-R1) has been recently shown to have antidepressant-like profile in rats. However, the mechanisms by which the MCHergic system participates in the modulation of emotional states are still to be determined.In the present study we confirmed the presence of MCHergic fibers within the dorsal raphe nucleus (DRN), a serotonergic nucleus involved in the physiopathology of major depression. We also assessed the effects of the administration of MCH and anti-MCH antibody (immunoneutralization) into the DRN using the forced swim test in rats, an animal model to screen antidepressant drugs. We found that a low dose of MCH (50ng) evoked a depressive-like behavior indicated by a significant increase in the immobility time as well as a decrease in climbing behavior. Furthermore, the depressive-like response was prevented by pretreatment with fluoxetine. Consistent with these results, the immunoneutralization of MCH produced an antidepressant-like effect. By means of the open field test we discarded that these effects were related to unspecific changes in motor activity.Our results suggest that the MCHergic neurons are involved in the regulation of emotional behaviors through the modulation of the serotonergic neuronal activity within the DRN. In addition, the present results are in agreement with previous reports showing that antagonism of the MCHergic system may be a novel therapeutic strategy for the treatment of depressive disorders.

Mice lacking Melanin Concentrating Hormone 1 receptor are resistant to seizures

The Melanin Concentrating Hormone (MCH) system is widely expressed throughout the central nervous system and regulates a variety of physiological functions. It has been reported that acute central administration of MCH inhibits pentylenetetrazol (PTZ)-induced seizures in rats. In the present study MCH1 receptor knockout mice (MCH1R-KO) were used to investigate the role of MCH signaling in modulating seizure susceptibility. Seizure behaviors were compared between MCH1R-KO and wild type (MCH1R-WT) mice following administration of the convulsant compounds PTZ or pilocarpine. PTZ injection induced clonic seizures in MCH1R-WT mice but failed to induce them in MCH1R-KO mice. More than twice as many injections of intermittently administered low dose PTZ were required to induce clonic seizures in MCH1R-KO mice than in MCH1R-WT mice. Following pilocarpine injection, MCH1R-WT mice experienced clonic seizures and most had tonic seizures and entered status epilepticus, while all MCH1R-KO mice were completely resistant to these effects. MCH1R-KO mice were also observed to be strongly protected from the development of PTZ kindling. Genetic deletion of MCH1R conferred resistance to all seizure models tested in this study. The data indicate that the MCH system is involved in the regulation of PTZ and pilocarpine seizure threshold.

Anxiolytic Effects of the MCH1R Antagonist TPI 1361-17

Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that acts on the MCH1 receptor. MCH1R is expressed widely throughout the brain, particularly in regions thought to be involved in the regulation of stress and emotional response. The role of MCH in anxiety has been controversial, however. Central administration of MCH has been reported to promote or reduce anxiety-like behaviors. The anxiolytic activity of several MCH1R antagonists has also been debated. To address this issue, we have tested whether TPI 1361-17, a highly specific and high affinity MCH1R antagonist, exerts anxiolytic effects in two commonly used models of anxiety, the elevated plus maze and the light–dark transition test. We show that this MCH1R antagonist exerts potent anxiolytic effects in both assays. Our study therefore supports previous studies indicating that MCH1R antagonists may be useful in the treatment of anxiety.