Elsevier

Biological Psychiatry

Volume 64, Issue 3, 1 August 2008, Pages 184-191
Biological Psychiatry

Archival Report
Dysregulation of the Mesolimbic Dopamine System and Reward in MCH−/− Mice

https://doi.org/10.1016/j.biopsych.2007.12.011Get rights and content

Background

The hypothalamic neuropeptide melanin-concentrating hormone (MCH) plays a critical role in energy homeostasis. Abundant expression of the MCH receptor is observed outside the hypothalamus, especially in the dorsal and the ventral striatum, raising the possibility that MCH modulates the function of the midbrain dopamine neurons and associated circuitry.

Methods

The MCH receptor 1 (MCHR1) expression was assessed by in situ hybridization. Expression of dopamine transporter (DAT) and the dopamine D1 and D2 receptor (D1R and D2R) subtypes in the caudate-putamen (CPu) and the nucleus accumbens (Acb) was evaluated by immunoblotting. Amperometry in ex vivo slices of the Acb was used to measure evoked-dopamine release in MCH−/ − mice. Catalepsy in MCH+/+ and MCH−/− mice was assessed by the bar test after haloperidol injection. Locomotor activity was measured after acute and chronic treatment with amphetamine and after dopamine reuptake inhibitor GBR 12909 administration.

Results

The psychostimulant amphetamine caused enhanced behavioral sensitization in MCH−/− mice. We found significantly elevated expression of the DAT in the Acb of MCH−/− mice. The DAT-mediated uptake of dopamine was also enhanced in MCH−/− mice consistent with increased expression of DAT. We also found that evoked dopamine release is significantly increased in the Acb shell of MCH−/− mice. The GBR 12909 administration increased the locomotor activity of MCH−/− mice significantly above that of MCH+/+ mice.

Conclusions

These results demonstrate that MCH, in addition to its known role in feeding and weight regulation, plays a critical role in regulating Acb dopamine signaling and related behavioral responses.

Section snippets

Animals

The MCH−/− and MCH+/+ littermates were bred under our direction at Taconic (Hudson, New York). The MCH−/− mice were originally generated by the Maratos-Flier group, and the physiology of these mice has been characterized (7, 13). Mice used in this study had been backcrossed onto the C57BL6 background for at least 15 generations. Colonies are maintained as het × het breeders, progeny is genotyped, and MCH+/+ and MCH−/− animals were shipped to us and individually housed in the Beth Israel

MCHR1 Is Highly Expressed in the Ventral Striatum But Not in the Ventral Tegmental Area

Expression of MCHR1 in mouse brain was determined by in situ hybridization of antisense riboprobe according to published procedures (25). A strong signal was detected in the terminal regions of dopaminergic projections from the midbrain, especially in the ventral striatum, Acb, and the olfactory tubercle (Tu) (Figures 1A and 1B). The PFC and prelimbic (PrL) and infralimbic (IL) cortex showed intermediate levels of MCHR1 expression. More caudally, expression increased in the medial shell of the

Discussion

Food intake is a complex behavior requiring integration of both homeostatic and hedonic inputs (34). Homeostatic signals provide information on energy status, whereas hedonic inputs mediate the rewarding aspects of feeding. Both inputs are essential, because animals must both perceive hunger and in consequence engage in activities that result in finding and consuming a meal. Furthermore, recent reports describe effects of peptides such as leptin (35, 36) and ghrelin (37) on dopaminergic

References (42)

  • J.D. Hommel et al.

    Leptin receptor signaling in midbrain dopamine neurons regulates feeding

    Neuron

    (2006)
  • T.M. Tzschentke

    Pharmacology and behavioral pharmacology of the mesocortical dopamine system

    Prog Neurobiol

    (2001)
  • A. Tyhon et al.

    Mice lacking the melanin-concentrating hormone receptor-1 exhibit an atypical psychomotor susceptibility to cocaine and no conditioned cocaine response

    Behav Brain Res

    (2006)
  • J.C. Bittencourt et al.

    The melanin-concentrating hormone system of the rat brain: An immuno- and hybridization histochemical characterization

    J Comp Neurol

    (1992)
  • C. Broberger et al.

    Hypocretin/orexin- and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: Relationship to the neuropeptide Y and agouti gene-related protein systems

    J Comp Neurol

    (1998)
  • D. Qu et al.

    A role for melanin-concentrating hormone in the central regulation of feeding behaviour

    Nature

    (1996)
  • M. Rossi et al.

    Melanin-concentrating hormone acutely stimulates feeding, but chronic administration has no effect on body weight

    Endocrinology

    (1997)
  • M. Ito et al.

    Characterization of MCH-mediated obesity in mice

    Am J Physiol Endocrinol Metab

    (2003)
  • D.S. Ludwig et al.

    Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance

    J Clin Invest

    (2001)
  • M. Shimada et al.

    Mice lacking melanin-concentrating hormone are hypophagic and lean

    Nature

    (1998)
  • Y. Saito et al.

    Molecular characterization of the melanin-concentrating-hormone receptor

    Nature

    (1999)
  • Cited by (65)

    • Conditional deletion of melanin-concentrating hormone receptor 1 from GABAergic neurons increases locomotor activity

      2019, Molecular Metabolism
      Citation Excerpt :

      Results from whole animals are also consistent with increased dopaminergic tone. MCH- and MCHR1-deficient mice display enhanced sensitization to psychostimulants like amphetamine [11,17,19] and cocaine [20,42], as well as increased locomotor responses to the dopamine reuptake blocker GBR12909 [11,20]. We found that in addition to recapitulating the hyperactivity in global MCH- or MCHR-deficient mice, MCHR1 deletion from vGAT neurons in our mice also increased dopaminergic tone, and they were more sensitive to the hyperlocomotor effects of GBR12909.

    • Diversity in the lateral hypothalamic input to the ventral tegmental area

      2019, Neuropharmacology
      Citation Excerpt :

      Leptin's effects on VTA projecting LHMCH neurons were attenuated by diet-induced obesity and by fasting (Liu et al., 2017), suggesting that synaptic input modulating VTA-projecting LHMCH neurons is sensitive to energy fluxes. While it is unclear if the LHMCH projection to the VTA can modulate mesolimbic dopamine release in the NAc, it is likely that LHMCH can alter dopaminergic neurons through activity at terminals in the NAc or on medium spiny neurons, where high levels of MCH receptors are expressed (Brown et al., 2015; Chee et al., 2013; Pissios et al., 2008; Saito et al., 2001). Indeed, LHMCH projections to the NAc modulate appetitive behaviour (Georgescu et al., 2005).

    • Hypothalamic neuropeptide signaling in alcohol addiction

      2016, Progress in Neuro-Psychopharmacology and Biological Psychiatry
      Citation Excerpt :

      In contrast to the reward-promoting effects of GAL, ENK, and OX, the ability of MCH to promote alcohol drinking may be due to its induction of dysphoria. Mice lacking the MCHR1 show greater evoked DA release from the NAc shell (Pissios et al., 2008), suggesting that activation of the MCHR1 normally inhibits these levels. Moreover, hypothalamic MCH gene expression positively correlates with aversive responses, including conditioned taste aversion (Mitra et al., 2012) and immobility in a forced swim test (Garcia-Fuster et al., 2012).

    View all citing articles on Scopus
    View full text