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.

Melanin-concentrating hormone (MCH) is a 19-amino-acid cyclic peptide which was originally found to lighten skin color in fish that is highly conserved among many species. MCH interacts with two G-protein-coupled receptors, MCH1R and MCH2R, but only MCH1R is expressed in rodents. MCH is mainly synthesized in the lateral hypothalamus and zona incerta, while MCH1R is widely expressed throughout the brain. Thus, MCH signaling is implicated in the regulation of many physiological functions. The identification of MCH1R has led to the development of small-molecule MCH1R antagonists that can block MCH signaling. MCH1R antagonists are useful not only for their potential therapeutic value, but also for understanding the physiological functions of the endogenous MCH system. Here, we review the physiological functions of the MCH system which have been investigated using MCH1R antagonists such as food intake, anxiety, depression, reward, and sleep. This will help us understand the physiological functions of the MCH system and suggest some of the potential applications of MCH1R antagonists in human disorders.

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 most neuropeptides are poorly understood. To gain insight into how neuropeptides regulate the MCH system, we investigated which neuropeptide receptors are expressed by MCH neurons by using double in situ hybridization. In all, 20 receptors, selected based on 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, 11 neuropeptide receptors were found to exhibit significant colocalization with MCH neurons: nociceptin/orphanin FQ opioid receptor (NOP), MCHR1, both orexin receptors (ORX), somatostatin receptors 1 and 2 (SSTR1, SSTR2), kisspeptin recepotor (KissR1), neurotensin receptor 1 (NTSR1), neuropeptide S receptor (NPSR), cholecystokinin receptor A (CCKAR), and the κ-opioid receptor (KOR). Among 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.

Melanin-concentrating hormone (MCH)-producing neurons are known to regulate a wide variety of physiological functions such as feeding, metabolism, anxiety and depression, and reward. Recent studies have revealed that MCH neurons receive projections from several wake-promoting brain regions and are integral to the regulation of rapid eye movement (REM) sleep. Here, we provide evidence in both rats and mice that MCH neurons express histamine-3 receptors (H3R), but not histamine-1 (H1R) or histamine-2 (H2R) receptors. Electrophysiological recordings in brain slices from a novel line of transgenic mice that specifically express the reporter ZsGreen in MCH neurons show that histamine strongly inhibits MCH neurons, an effect which is TTX insensitive, and blocked by the intracellular presence of GDP-β-S. A specific H3R agonist, α-methylhistamine, mimicks the inhibitory effects of histamine, and a specific neutral H3R antagonist, VUF 5681, blocks this effect. Tertiapin Q (TPQ), a G protein-dependent inwardly rectifying potassium (GIRK) channel inhibitor, abolishes histaminergic inhibition of MCH neurons. These results indicate that histamine directly inhibits MCH neurons through H3R by activating GIRK channels and suggest that that inhibition of the MCH system by wake-active histaminergic neurons may be responsible for silencing MCH neurons during wakefulness and thus may be directly involved in the regulation of sleep and arousal.

The dual hypocretin receptor (HcrtR) antagonist almorexant (ALM) may promote sleep through selective disfacilitation of wake-promoting systems, whereas benzodiazepine receptor agonists (BzRAs) such as zolpidem (ZOL) induce sleep through general inhibition of neural activity. Previous studies have indicated that HcrtR antagonists cause less-functional impairment than BzRAs. To gain insight into the mechanisms underlying these differential profiles, we compared the effects of ALM and ZOL on functional activation of wake-promoting systems at doses equipotent for sleep induction. Sprague-Dawley rats, implanted for EEG/EMG recording, were orally administered vehicle (VEH), 100 mg/kg ALM, or 100 mg/kg ZOL during their active phase and either left undisturbed or kept awake for 90 min after which their brains were collected. ZOL-treated rats required more stimulation to maintain wakefulness than VEH- or ALM-treated rats. We measured Fos co-expression with markers for wake-promoting cell groups in the lateral hypothalamus (Hcrt), tuberomammillary nuclei (histamine; HA), basal forebrain (acetylcholine; ACh), dorsal raphe (serotonin; 5HT), and singly labeled Fos(+) cells in the locus coeruleus (LC). Following SD, Fos co-expression in Hcrt, HA, and ACh neurons (but not in 5HT neurons) was consistently elevated in VEH- and ALM-treated rats, whereas Fos expression in these neuronal groups was unaffected by SD in ZOL-treated rats. Surprisingly, Fos expression in the LC was elevated in ZOL- but not in VEH- or ALM-treated SD animals. These results indicate that Hcrt signaling is unnecessary for the activation of Hcrt, HA, or ACh wake-active neurons, which may underlie the milder cognitive impairment produced by HcrtR antagonists compared to ZOL.