Behavioural analysis of melanin-concentrating hormone in rats: evidence for orexigenic and anxiolytic properties

Kela, Johanna; Salmi, Peter; Rimondini, Roberto; Heilig, Markus; Wahlestedt, Claes

doi:10.1016/s0167-0115(03)00114-9

Cited by 61 publications

(37 citation statements)

References 34 publications

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“…Modulation of anxiety-like behavioral responses has also been observed following i.c.v. injections of the MCH ligand (Gonzalez et al, 1996;Kela et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Although the widespread innervations of MCH-containing fibers and the expression of MCHR1 in brain areas such as the hippocampus, basolateral amygdala, and prefrontal cortex (PFC) (Saito et al, 2001) suggests potential involvement in the control of emotion and cognition, only a few reports have directly addressed this issue. Intracranial MCH administration has been shown to regulate response to novelty (Monzon et al, 2001;Kela et al, 2003) and learning and memory . In the most suggestive study to date, acute systemic administration of a selective MCHR1 receptor antagonist to rodents elicited both anxiolytic-and antidepressant-like effects (Borowsky et al, 2002;Chaki et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Genetic Inactivation of Melanin-Concentrating Hormone Receptor Subtype 1 (MCHR1) in Mice Exerts Anxiolytic-Like Behavioral Effects

Roy

David

Danao

et al. 2005

Neuropsychopharmacol

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The biological effects of the melanin-concentrating hormone (MCH) are mediated by the melanin concentrating hormone receptor 1 (MCHR1) in mice. This receptor is enriched in brain areas that are involved in the modulation of mood and affect, suggesting that MCHdependent signaling may influence neurobiological mechanisms underlying fear and anxiety processes. To test this, we have generated mice lacking functional MCHR1 and characterized phenotypic traits using a number of behavioral tests. Mice carrying a null mutation of the MCHR1 gene display anxiolytic-like behavior across a battery different behavioral paradigms commonly used to assess fear and anxiety responses in rodents: open field, elevated plus maze, social interaction, and stress-induced hyperthermia. The brain serotonin (5-HT) system is central to the control of mood-and anxiety-related processes. To examine the impact of MCHR1 receptor deletion on 5-HT neurotransmission, we used in vivo microdialysis in freely moving knockout and wild-type mice. Baseline dialysate 5-HT levels were significantly lower in MCHR1 knockout mice as compared with wild-type controls (9.5370.24 fmol for wild types vs 6.9170.36 fmol for knockouts) in the prefrontal cortex (PFC), one of the main target structures of the serotonergic system and one that is highly associated with the control of emotional processes. Moreover, forced swim increased 5-HT efflux in the PFC of wild-type but not MCHR1 knockout mice. In summary, we show that MCHR1 can modulate stress-and anxiety-like behaviors and suggest that this may be due to changes in serotonergic transmission in forebrain regions.

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“…Modulation of anxiety-like behavioral responses has also been observed following i.c.v. injections of the MCH ligand (Gonzalez et al, 1996;Kela et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetic Inactivation of Melanin-Concentrating Hormone Receptor Subtype 1 (MCHR1) in Mice Exerts Anxiolytic-Like Behavioral Effects

Roy

David

Danao

et al. 2005

Neuropsychopharmacol

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show abstract

“…In the elevated plus maze (EPM), intracerebroventricular (i.c.v.) 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: 99%

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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“…Central administration of MCH has anxiolytic effects in the elevated plus-maze and the Vogel punished drinking test (248,249). In contrast, an MCH1-R antagonist has been shown to reduce anxiety in the social interaction test and depression in the forced swim test (FST) (250).…”

Section: Mch In Modulation Of Stress and Anxietymentioning

confidence: 99%

“…The role of MCH and the MCH1-R in energy balance and homeostasis is well established (217,248,251). The MCH1-R antagonist GW803430 has been shown to attenuate alcohol selfadministration and block cue-induced reinstatement of alcohol seeking in naïve rats.…”

Section: Melanin-concentrating Hormone and Its Mch1 Receptormentioning

confidence: 99%

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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Behavioural analysis of melanin-concentrating hormone in rats: evidence for orexigenic and anxiolytic properties

Cited by 61 publications

References 34 publications

Genetic Inactivation of Melanin-Concentrating Hormone Receptor Subtype 1 (MCHR1) in Mice Exerts Anxiolytic-Like Behavioral Effects

Genetic Inactivation of Melanin-Concentrating Hormone Receptor Subtype 1 (MCHR1) in Mice Exerts Anxiolytic-Like Behavioral Effects

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

Neuropeptide Receptors as Treatment Targets in Alcohol Use Disorders

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