Effect of Direct Injection of Melanin‐Concentrating Hormone into the Paraventricular Nucleus: Further Evidence for a Stimulatory Role in the Adrenal Axis via SLC‐1

Kennedy, Alice; Todd, Jeannie F; Dhillo, Waljit S.; Ghatei, M.A.; O'Toole, Christine M.B.; Jones, Marshall; Witty, David R.; Winborne, K.; Riley, Graham J.; Hervieu, Guillaume; Wilson, Shelagh; Bloom, Stephen R.

doi:10.1046/j.1365-2826.2003.00997.x

Cited by 84 publications

(66 citation statements)

References 36 publications

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“…MCH injected directly into the lateral ventricle or the PVN stimulated the HPA axis (Jezova et al, 1992;Kennedy et al, 2003), and MCHR1 antagonists resembled known antidepressant and anxiolytic drugs (Borowsky et al, 2002;Chaki et al, 2005). Our data support these findings and expand on them by demonstrating a direct relationship between the anxiogenic effects of MCH and the reversal of these effects by selective MCHR1 blockade.…”

Section: Discussionsupporting

confidence: 81%

“…infusion of MCH was reported to have either anxiogenic- (Gonzalez et al, 1996) or anxiolytic-like (Kela et al, 2003;Monzon and De Barioglio, 1999;Monzon et al, 2001) effects. Finally, novel MCHR1 antagonists blocked MCH-induced release of corticotrophin-releasing factor (Kennedy et al, 2003), and resembled known anxiolytics and antidepressants in animal models (Borowsky et al, 2002;Chaki et al, 2005).…”

Section: Introductionmentioning

confidence: 86%

“…MCH injected directly into the lateral ventricle or the paraventricular nucleus (PVN) of the hypothalamus stimulated the hypothalamic-pituitary-adrenocortical (HPA) axis in some experiments (Jezova et al, 1992; Kennedy et al, 2003), but blocked stress-induced activation of the HPA axis in other studies (Bluet-Pajot et al, 1995;Ludwig et al, 1998). In the elevated plus maze (EPM), intracerebroventricular (i.c.v.)…”

Section: Introductionmentioning

confidence: 99%

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

Smith

Davis

Rorick-Kehn

et al. 2005

Neuropsychopharmacol

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Repeated exposure to stressful conditions is linked to the etiology of affective disorders. The melanin-concentrating hormone-1 receptor (MCHR1) may be a novel mechanism that is involved in the modulation of stress responses and affective states. The role of MCHR1 in neuroendocrine, behavioral, and neurochemical stress, and anxiety-related responses was examined by monitoring the effects of melanin-concentrating hormone (MCH) and the selective MCHR1 antagonist, GW3430, in inbred C57Bl/6NTac and MCHR1-knockout (KO) and wild-type (WT) mice. Intracerebroventricular injection of MCH increased plasma corticosterone, and produced anxiety-related responses in the elevated plus maze. The selective MCHR1 antagonist, GW3430, blocked the neuroendocrine and behavioral effects of MCH and produced anxiolytic-like effects by itself in animal models of anxiety. Moreover, KO mice had an anxiolytic-like phenotype in behavioral models of anxiety, and GW3430 had anxiolytic-like effects in WT, but not KO mice. Lastly, stressor-evoked acetylcholine release within the prefrontal cortex of inbred and WT mice, but not KO mice, was blocked by GW3430. We show that MCH elicits anxiety-like responses and that the effects of a selective MCHR1 antagonist and the phenotype of KO mice are consistent with anxiolyticlike action. Distinct behavioral, physiological, and neurochemical stress, and anxiety-related responses were selectively modulated by the MCHR1, and these actions may involve corticolimbic regulation of stress responsivity and anxiety.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

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

Smith

Davis

Rorick-Kehn

et al. 2005

Neuropsychopharmacol

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“…Local injection of MCH into the paraventricular nucleus of the hypothalamus (PVN) elevates ACTH and plasma corticosterone in rats. These results suggest that MCH can activate the HPA via CRH system (246). Abnormalities in HPA axis function have been associated with depression, chronic stress and AUD (247).…”

Section: Mch In Modulation Of Stress and Anxietymentioning

confidence: 94%

Neuropeptide Receptors as Treatment Targets in Alcohol Use Disorders

Aziz¹

2017

Linköping University Medical Dissertations

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Alcohol use disorder (AUD) is a complex disorder with multiple pathophysiological processes contributing to the initiation, progression and development of the disease state. AUD is a chronic relapsing disease with escalation of alcohol-intake over time in repeated cycles of tolerance, abstinence and relapse and hence, it is very difficult to treat. There are only a few currently available treatments with narrow efficacy and variable patient response. Thus it is important to find new, more effective medications to increase the number of patients who can benefit from pharmacological treatment of AUD.The research presented in this thesis work focuses on the critical involvement of central neuropeptides in alcohol-related behaviors. The overall aim was to evaluate the nociceptin/orphanin FQ (NOP) receptor, the neuropeptide Y (NPY) Y2 receptor and the melanin-concentrating hormone (MCH) receptor 1 as novel and potential pharmacological treatment targets for AUD by testing the NOP receptor agonist SR-8993, the NPY-Y2 receptor antagonist CYM-9840 and the MCH1 receptor antagonist GW803430 in established animal models.In the first study (Paper I), the novel and selective NOP agonist SR-8993 was assessed in rat models of motivation to obtain alcohol and relapse to alcohol-seeking behavior using the operant self-administration (SA) paradigm. Firstly, treatment with SR-8993 (1 mg/kg) showed a mildly anxiolytic effect and reversed acute alcohol withdrawal-induced "hangover" anxiety in the elevated plus-maze (EPM). Next, it potently attenuated alcohol SA and motivation to obtain alcohol in the progressive ratio responding (PRR) and reduced both alcohol cue-induced and yohimbine stressinduced reinstatement of alcohol seeking, without affecting the pharmacology and metabolism of alcohol nor other control behaviors. To extend these findings, SR-8993 was evaluated in escalated alcohol-intake in rats. Treatment with SR-8993 significantly suppressed alcohol-intake and preference in rats that were trained to consume high amounts of alcohol in the two-bottle free choice intermittent access (IA) paradigm. SR-8993 also blocked operant SA of alcohol in rats that showed robust escalation in operant alcohol SA following chronic IA exposure to alcohol.In the second study (Paper II), SR-8993 was further evaluated in a model for escalated alcohol-intake induced by long-term IA exposure to alcohol. The effect of previous experience on operant alcohol SA on two-bottle free choice preference drinking was evaluated and sensitivity to treatment with SR-8993 was tested in rats selected for escalated and non-escalated alcohol seeking behavior. We found that rats exposed to the combined SA-IA paradigm showed greater sensitivity to SR-8993 treatment. In addition, acute escalation of alcohol SA after a three-week period of abstinence was completely abolished by pretreatment with SR-8993.In the third study (Paper III), the effects of the novel, small molecule NPY-Y2 antagonist CYM-9840 were tested in operant alcohol SA, PRR which is a model for...

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“…Yet, there is no in vitro or in vivo evidence to support the compound penetrates the brain. Further evidence in support of the hypothesis relies on direct injection of MCH or MCH antagonists into the hypothalamus followed by evaluation of food intake and body weight (Bednarek et al, 2002;Hervieu, 2003;Kennedy et al, 2003;Shearman et al, 2003). Although informative, these data only indicate that the hypothalamus is one site of action for MCH and MCH antagonists, leaving open the role of the peripheral MCH1Rs.…”

Section: Downloaded Frommentioning

confidence: 99%

Small-Molecule Melanin-Concentrating Hormone-1 Receptor Antagonists Require Brain Penetration for Inhibition of Food Intake and Reduction in Body Weight

Wos

Dowty

et al. 2007

J Pharmacol Exp Ther

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The melanin-concentrating hormone-1 receptor (MCH1R) is a G-protein-coupled receptor expressed in the brain and peripheral tissues that regulates energy storage and body weight. Here, we focused on discovery of the mechanism and site of action for a small-molecule MCH1R antagonist, which yields weight loss in a mouse model of human obesity. MCH1R is expressed throughout the brain but also found in peripheral tissues known to regulate fat storage and utilization, e.g., skeletal muscle and adipose tissue. Previous studies of MCH1R antagonist studies have not delineated the site that is critical for mediating the anorexigenic and weight-reducing actions. In this study, we evaluated the role of the brain and peripheral tissue receptors. We developed a novel nonbrain-permeable MCH antagonist analog with a carboxylic acid moiety to specifically test the site of action. Based on in vitro and in vivo assays, the analog is not able to cross the blood-brain barrier and does not lead to inhibition of food intake and reduced body weight. The data clearly demonstrate that MCH1R antagonists need access to the brain to reduce body weight and fat mass. The brainpermeable MCH1R antagonist leads to significant reduction in body weight and fat mass in diet-induced obese mice. The effect is dose-dependent and appears to be partially driven by a reduction in food intake. Finally, these studies show the utility of a medicinal chemistry approach to address an important biological and pharmacological question.The obesity epidemic continues to increase in many developed and developing countries (Ogden et al., 2003;Haslam and James, 2005). The 2004 National Health and Nutrition Examination Survey indicated that more than 50% of the United States population is either obese or overweight (Hedley et al., 2004;Ogden et al., 2006). More importantly, the incidence of obese and overweight children is also on the rise. Obesity is associated with multiple metabolic disorders, including diabetes and cardiovascular disease (Ogden et al., 2003). There is a great interest in identifying behavioral and pharmacological approaches to reduce body weight in obese and overweight individuals.Weight loss intervention strategies include targets for reducing hunger/appetite, enhancing satiety, increasing metabolism/ energy utilization, blocking fat absorption, inhibiting adipose tissue differentiation, and inducing adipose tissue apoptosis. The current therapeutic approaches for weight loss include diet, exercise, and pharmacotherapy. Efficacy is very modest, with a high rate of recidivism at the end of the treatment period (Schnee et al., 2006). Orlistat (Xenical) and sibutramine (Meridia) are currently the only two approved pharmacotherapy agents on the market. Orlistat blocks absorption of fat from the intestine, whereas sibutramine reduces appetite by acting on brain pathways that regulate hunger (Bray and Ryan, 2007). These drugs show limited efficacy, and considerable attention is focused on the development of new reagents to decrease body weight.

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Effect of Direct Injection of Melanin‐Concentrating Hormone into the Paraventricular Nucleus: Further Evidence for a Stimulatory Role in the Adrenal Axis via SLC‐1

Cited by 84 publications

References 36 publications

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

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

Neuropeptide Receptors as Treatment Targets in Alcohol Use Disorders

Small-Molecule Melanin-Concentrating Hormone-1 Receptor Antagonists Require Brain Penetration for Inhibition of Food Intake and Reduction in Body Weight

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