Melanin-Concentrating Hormone-1 Receptor Modulates Neuroendocrine, Behavioral, and Corticolimbic Neurochemical Stress Responses in Mice

Smith, Daniel G.; Davis, R. J.; Rorick-Kehn, Linda; Morin, Mario; Witkin, Jeffrey M.; McKinzie, David L.; Nomikos, George G.; Gehlert, Donald R.

doi:10.1038/sj.npp.1300913

Cited by 100 publications

(87 citation statements)

References 45 publications

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“…Therefore, the CPP score under a biased CPP procedure represents not only the motivation for cocaine, but also the overcoming of the anxiety experienced in the conditioning compartment. However, the unbiased design used in our CPP experiments excludes the anxiety factor, an important factor, because the MCH system has been reported to regulate anxiety (37,38), and MCH1RKO mice tend to be less anxious (38). Therefore, we suggest that the differences in CPP results derive from differences in the designs of the assays.…”

Section: Discussionmentioning

confidence: 98%

The melanin-concentrating hormone system modulates cocaine reward

Chung

Hopf

Nagasaki

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

130

140

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Drug addiction is mediated by complex neuronal processes that converge on the shell of the nucleus accumbens (NAcSh). The NAcSh receives inputs from the lateral hypothalamus (LH), where selfstimulation can be induced. Melanin-concentrating hormone (MCH) is produced mainly in the LH, and its receptor (MCH1R) is highly expressed in the NAcSh. We found that, in the NAcSh, MCH1R is coexpressed with dopamine receptors (D1R and D2R), and that MCH increases spike firing when both D1R and D2R are activated. Also, injecting MCH potentiates cocaine-induced hyperactivity in mice. Mice lacking MCH1R exhibit decreased cocaine-induced conditioned place preference, as well as cocaine sensitization. Using a specific MCH1R antagonist, we further show that acute blockade of the MCH system not only reduces cocaine self-administration, but also attenuates cue-and cocaine-induced reinstatement. Thus, the MCH system has an important modulatory role in cocaine reward and reinforcement by potentiating the dopaminergic system in the NAcSh, which may provide a new rationale for treating cocaine addiction.T he shell of the nucleus accumbens (NAcSh) is known to be an important center for reward and motivation. It is a major terminal area of the mesolimbic dopamingergic system, which projects from the ventral tegmental area (VTA) (1). The NAcSh neurons express both dopamine D1 and D2 receptors, which have opposite effects on cAMP-dependent signaling; however, motivated behaviors require concomitant D1 and D2 receptor signaling in the NAcSh (2). The NAcSh receives inputs from different brain areas, in particular, from the lateral hypothalamus (LH) (3). The importance of the LH in reward and motivation has been shown by Olds (4), who discovered that electrical activation of the LH induced an extraordinarily intense self-stimulation response in rats. However, the transmitter(s) responsible for this action have not been established definitively. We now know of 2 neuropeptides that are uniquely synthesized in the LH: the orexins/hypocretins (5), and melanin-concentrating hormone (MCH) (6-8). The orexin/ hypocretin neurons do not project prominently to the NAcSh, whereas the MCH neurons do (9). This data suggested to us that the MCH system may regulate the activities of the NAcSh neurons to influence reward.MCH is a cyclic, 19-amino acid peptide originally isolated from salmon pituitary as a melanophore-concentrating factor (10). It is also present in rats and humans (11,12), where it is viewed as important in regulating nutritional homeostasis (8, 13). In mammals, MCH is expressed predominantly centrally, and occurs only in 2 nuclei: the perikarya of the LH area (LHA), and the zona incerta (ZI). However, MCH fibers project in many areas throughout the CNS (6, 9), indicating that the MCH system may have a broad range of physiological roles. In rodents, MCH is known to interact with one G protein-coupled receptor, MCH1R (14-18). MCH1R is expressed in many brain regions (9), and the NAcSh has one of the highest MCH1R expression levels. Indeed, the ...

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Section: Discussionmentioning

confidence: 98%

The melanin-concentrating hormone system modulates cocaine reward

Chung

Hopf

Nagasaki

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

130

140

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“…After the baseline period, mice were placed in a bucket that contained soiled bedding from rat cages for a period of 60 min, whereas four additional hippocampal dialysate samples were collected. The predatory odor stress test was used to determine the effects of stress on hippocampal ACh in WT and KO mice, because exposure of mice to predatory odors has been shown previously to result in robust increases in cortical/hippocampal ACh efflux (Smith et al, 2005).…”

Section: Surgical Proceduresmentioning

confidence: 99%

CB₁Receptor Antagonism Increases Hippocampal Acetylcholine Release: Site and Mechanism of Action

Degroot

Köfalvi²,

Wade³

et al. 2006

Mol Pharmacol

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Evidence indicates that blockade of cannabinoid receptors increases acetylcholine (ACh) release in brain cortical regions. Although it is assumed that this type of effect is mediated through CB 1 receptor (CB 1 R) antagonism, several in vitro functional studies recently have suggested non-CB 1 R involvement. In addition, neither the precise neuroanatomical site nor the exact mechanisms underlying this effect are known. We thoroughly examined these issues using a combination of systemic and local administration of CB 1 R antagonists, different methods of in vivo microdialysis, CB 1 R knockout (KO) mice, tissue measurements of ACh, and immunochemistry. First, we showed that systemic injections of the CB 1 R antagonists N-(pi-dose-dependently increased hippocampal ACh efflux. Likewise, local hippocampal, but not septal, infusions of SR141716A or AM251 increased hippocampal ACh release. It is noteworthy that the stimulatory effects of systemically administered CB 1 R antagonists on hippocampal ACh release were completely abolished in CB 1 R KO mice. CB 1 R KO mice had similar basal but higher stress-enhanced hippocampal ACh levels compared with wild-type controls. It is interesting that dopamine D 1 receptor antagonism counteracted the stimulatory effect of CB 1 R blockade on hippocampal ACh levels. Finally, immunohistochemical methods revealed that a high proportion of CB 1 R-positive nerve terminals were found in hippocampus and confirmed the colocalization of CB 1 receptors with cholinergic and dopaminergic nerve terminals. In conclusion, hippocampal ACh release may specifically be controlled through CB 1 Rs located on both cholinergic and dopaminergic neuronal projections, and CB 1 R antagonism increases hippocampal ACh release, probably through both a direct disinhibition of ACh release and an indirect increase in dopaminergic neurotransmission at the D 1 receptors.Animal studies have shown that cannabinoid receptor activation and blockade impair and enhance cognitive performance, respectively, under certain experimental conditions (Chaperon and Thiebot, 1999). These effects on cognition have been correlated with fluctuating extracellular acetylcholine (ACh) levels in the hippocampus, in which an abundance of cannabinoid receptors and cholinergic nerve terminals reside (Tzavara et al., 2003b;Inui et al., 2004). The effect of cannabinoid receptor stimulation on hippocampal ACh efflux can vary depending on dosage and site of administration. In general, high doses of cannabinoid agonists decrease whereas lower doses increase hippocampal ACh release, and these effects are mediated through the hippocampus and septum, respectively (Tzavara et al., 2003b). Two types of cannabinoid receptors have been identified: the cannabinoid receptor type 1 (CB 1 R) and type 2 (CB 2 R) (Devane et al., 1988). The modulation of hippocampal ACh levels induced by cannabinoids is probably mediated through CB 1 R given their distribution in the septohippocampal pathway (Howlett et al., 2004).The effect of cannabinoid receptor sti...

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“…In addition, direct delivery of another MCHR1 antagonist to the nucleus accumbens shell produced antidepressant-like activity in the FST, whereas intra-accumbens shell injection of MCH produced the opposite effect (Georgescu et al, 2005). More recently, a pretreatment with the MCHR1 antagonist GW3430 reversed the anxiogenic effects of MCH in the EPM and stress-induced hyperthermia tests and restored plasma corticosterone to control levels (Smith et al, 2006).…”

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confidence: 99%

Efficacy of the MCHR1 Antagonist N-[3-(1-{[4-(3,4-Difluorophenoxy)phenyl]methyl}(4-piperidyl))-4-methylphenyl]-2-methylpropanamide (SNAP 94847) in Mouse Models of Anxiety and Depression following Acute and Chronic Administration Is Independent of Hippocampal Neurogenesis

David¹,

Klemenhagen²,

Holick³

et al. 2007

J Pharmacol Exp Ther

122

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Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that plays a role in the modulation of food intake and mood. In rodents, the actions of MCH are mediated via the MCHR1 receptor. The goal of this study was to investigate the effects of acute (1 h) and chronic (28 days) p.o. dosing of a novel MCHR1 antagonist,phenyl]methyl}(4-piperidyl))-4-methylphenyl]-2-methylpropanamide (SNAP 94847), in three mouse models predictive of antidepressant/anxiolytic-like activity: novelty suppressed feeding (NSF) in 129S6/SvEvTac mice and light/dark paradigm (L/D) and forced swim test (FST) in BALB/cJ mice. A significant increase in the time spent in the light compartment of the L/D box was observed in response to acute and chronic treatment with SNAP 94847. An anxiolytic/antidepressant-like effect was found in the NSF test after acute and chronic treatment, whereas no effect was observed in the FST. Because neurogenesis in the dentate gyrus has been shown to be a requirement for the effects of antidepressants in the NSF test, we investigated whether neurogenesis was required for the effect of SNAP 94847. We showed that chronic treatment with SNAP 94847 stimulated proliferation of progenitors in the dentate gyrus. The efficacy of SNAP 94847 in the NSF test, however, was unaltered in mice in which neurogenesis was suppressed by X-irradiation. These results indicate that SNAP 94847 has a unique anxiolytic-like profile after both acute and chronic administration and that its mechanism of action is distinct from that of selective serotonin reuptake inhibitors and tricyclic antidepressants.Depression and anxiety are major causes of disability worldwide. The major obstacles faced in treating these disorders with selective serotonin reuptake inhibitors (SSRI) are that the therapeutic response develops slowly (3-4 weeks), side effects often occur, and there is a significant percentage of nonresponders (Ϸ30%) (Wong and Licinio, 2001). Neuropeptide receptors may offer alternative therapeutic targets for depression and anxiety disorders (Griebel, 1999), particularly those selectively localized in brain regions Article, publication date, and citation information can be found at

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Melanin-Concentrating Hormone-1 Receptor Modulates Neuroendocrine, Behavioral, and Corticolimbic Neurochemical Stress Responses in Mice

Cited by 100 publications

References 45 publications

The melanin-concentrating hormone system modulates cocaine reward

The melanin-concentrating hormone system modulates cocaine reward

CB₁Receptor Antagonism Increases Hippocampal Acetylcholine Release: Site and Mechanism of Action

Efficacy of the MCHR1 Antagonist N-[3-(1-{[4-(3,4-Difluorophenoxy)phenyl]methyl}(4-piperidyl))-4-methylphenyl]-2-methylpropanamide (SNAP 94847) in Mouse Models of Anxiety and Depression following Acute and Chronic Administration Is Independent of Hippocampal Neurogenesis

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Melanin-Concentrating Hormone-1 Receptor Modulates Neuroendocrine, Behavioral, and Corticolimbic Neurochemical Stress Responses in Mice

Cited by 100 publications

References 45 publications

The melanin-concentrating hormone system modulates cocaine reward

The melanin-concentrating hormone system modulates cocaine reward

CB1Receptor Antagonism Increases Hippocampal Acetylcholine Release: Site and Mechanism of Action

Efficacy of the MCHR1 Antagonist N-[3-(1-{[4-(3,4-Difluorophenoxy)phenyl]methyl}(4-piperidyl))-4-methylphenyl]-2-methylpropanamide (SNAP 94847) in Mouse Models of Anxiety and Depression following Acute and Chronic Administration Is Independent of Hippocampal Neurogenesis

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CB₁Receptor Antagonism Increases Hippocampal Acetylcholine Release: Site and Mechanism of Action