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

doi:10.1016/j.biopsych.2007.12.011

Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2007.12.011 Get 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

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The mesolimbic dopamine system is the primary neural circuit mediating motivation, reinforcement, and reward-related behavior. The activity of this system and multiple behaviors controlled by it are affected by changes in feeding and body weight, such as fasting, food restriction, or the development of obesity. Multiple different peptides and hormones that have been implicated in the control of feeding and body weight interact with the mesolimbic dopamine system to regulate many different dopamine-dependent, reward-related behaviors. In this review, we summarize the effects of a selected set of feeding-related peptides and hormones acting within the ventral tegmental area and nucleus accumbens to alter feeding, as well as food, drug, and social reward.
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Melanin-concentrating hormone (MCH) is a neuropeptide primarily transcribed in the lateral hypothalamus (LH), with vast projections to many areas throughout the central nervous system that play an important role in motivated behaviors and drug use. Anatomical, pharmacological and genetic studies implicate MCH in mediating the intake and reinforcement of commonly abused substances, acting by influencing several systems including the mesolimbic dopaminergic system, glutamatergic as well as GABAergic signaling and being modulated by inflammatory neuroimmune pathways. Further support for the role of MCH in controlling behavior related to drug use will be discussed as it relates to cerebral ventricular volume transmission and intracellular molecules including cocaine- and amphetamine-regulated transcript peptide, dopamine- and cAMP-regulated phosphoprotein 32 kDa. The primary goal of this review is to introduce and summarize current literature surrounding the role of MCH in mediating the intake and reinforcement of commonly abused drugs, such as alcohol, cocaine, amphetamine, nicotine and opiates.
Conditional deletion of melanin-concentrating hormone receptor 1 from GABAergic neurons increases locomotor activity
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This suggested that MCHR1 neurons within the accumbens nucleus mediate the effects of MCH on locomotor activity. Since both Mch-KO [11] and Vgat-Mchr1-KO (Figure 2E) mice show an enhanced sensitivity to dopamine-mediated hyperactivity, we sought to determine if MCH signaling directly interacts with the dopamine system of the accumbens nucleus. In order to measure dopamine release, we performed in vitro amperometry recordings in fresh brain slices containing the striatum and determined the peak current amplitude evoked by a stimulating electrode every five minutes.
Melanin-concentrating hormone (MCH) plays a key role in regulating energy balance. MCH acts via its receptor MCHR1, and MCHR1 deletion increases energy expenditure and locomotor activity, which is associated with a hyperdopaminergic state. Since MCHR1 expression is widespread, the neurons supporting the effects of MCH on energy expenditure are not clearly defined. There is a high density of MCHR1 neurons in the striatum, and these neurons are known to be GABAergic. We thus determined if MCH acts via this GABAergic neurocircuit to mediate energy balance.
We generated a Mchr1-flox mouse and crossed it with the Vgat-cre mouse to assess if MCHR1 deletion from GABAergic neurons expressing the vesicular GABA transporter (vGAT) in female Vgat-Mchr1-KO mice resulted in lower body weights or increased energy expenditure. Additionally, we determined if MCHR1-expressing neurons within the accumbens form part of the neural circuit underlying MCH-mediated energy balance by delivering an adeno-associated virus expressing Cre recombinase to the accumbens nucleus of Mchr1-flox mice. To evaluate if a dysregulated dopaminergic tone leads to their hyperactivity, we determined if the dopamine reuptake blocker GBR12909 prolonged the drug-induced locomotor activity in Vgat-Mchr1-KO mice. Furthermore, we also performed amperometry recordings to test whether MCHR1 deletion increases dopamine output within the accumbens and whether MCH can suppress dopamine release.
Vgat-Mchr1-KO mice have lower body weight, increased energy expenditure, and increased locomotor activity. Similarly, restricting MCHR1 deletion to the accumbens nucleus also increased locomotor activity. Vgat-Mchr1-KO mice show increased and prolonged sensitivity to GBR12909-induced locomotor activity, and amperometry recordings revealed that GBR12909 elevated accumbens dopamine levels to twice that of controls, thus MCHR1 deletion may lead to a hyperdopaminergic state that mediates their observed hyperactivity. Consistent with the inhibitory effect of MCH, we found that MCH acutely suppresses dopamine release within the accumbens.
As with established models of systemic MCH or MCHR1 deletion, we found that MCHR1 deletion from GABAergic neurons, specifically those within the accumbens nucleus, also led to increased locomotor activity. A hyperdopaminergic state underlies this increased locomotor activity, and is consistent with our finding that MCH signaling within the accumbens nucleus suppresses dopamine release. In effect, MCHR1 deletion may disinhibit dopamine release leading to the observed hyperactivity.
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The obesity epidemic is one of the biggest health challenges globally and rates have tripled since 1975. Overeating is the largest determinant of obesity, yet little is understood of the neural mechanisms underlying why individuals consume food regardless of satiety. The lateral hypothalamic (LH) input to the ventral tegmental area (VTA) has been critically implicated in regulating appetitive and reward-related behaviours. However, these projections are genetically heterogeneous and have different responses to leptin. Therefore each of these projections may play a different role in modulating the VTA. This review characterizes each of these known LH to VTA projections in their roles in regulating appetitive behaviour.
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For example, the melanin-concentrating hormone (MCH −/−) knockout mouse is lean compared with its wild-type littermates (Shimada et al., 1998). MCH is an appetite-promoting hypothalamic neuropeptide, and the reduced food intake and dysregulation of dopamine neurotransmission in the MCH −/− mouse contribute to its lean phenotype (Pissios et al., 2008). Based on this phenotype, antagonism of the MCH-1 receptor, which should have a similar effect on feeding behavior as seen in the MCH −/− mouse, is one approach that researchers are pursuing in the development of obesity therapeutics (Macneil, 2013).
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Hypothalamic neuropeptide signaling in alcohol addiction
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The hypothalamus is now known to regulate alcohol intake in addition to its established role in food intake, in part through neuromodulatory neurochemicals termed neuropeptides. Certain orexigenic neuropeptides act in the hypothalamus to promote alcohol drinking, although they affect different aspects of the drinking response. These neuropeptides, which include galanin, the endogenous opioid enkephalin, and orexin/hypocretin, appear to stimulate alcohol intake not only through mechanisms that promote food intake but also by enhancing reward and reinforcement from alcohol. Moreover, these neuropeptides participate in a positive feedback relationship with alcohol, whereby they are upregulated by alcohol intake to promote even further consumption. They contrast with other orexigenic neuropeptides, such as melanin-concentrating hormone and neuropeptide Y, which promote alcohol intake under limited circumstances, are not consistently stimulated by alcohol, and do not enhance reward. They also contrast with neuropeptides that can be anorexigenic, including the endogenous opioid dynorphin, corticotropin-releasing factor, and melanocortins, which act in the hypothalamus to inhibit alcohol drinking as well as reward and therefore counter the ingestive drive promoted by orexigenic neuropeptides. Thus, while multiple hypothalamic neuropeptides may work together to regulate different aspects of the alcohol drinking response, excessive signaling from orexigenic neuropeptides or inadequate signaling from anorexigenic neuropeptides can therefore allow alcohol drinking to become dysregulated.

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

Background

Methods

Results

Conclusions

Section snippets

Animals

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

Discussion

Eur J Pharmacol

Regul Pept

Physiol Behav

Neuron

Brain Res Brain Res Rev

Neurosci Biobehav Rev

Eur J Pharmacol

J Biol Chem

Neuron

Neuron

Neuron

Prog Neurobiol

Behav Brain Res

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

J Comp Neurol

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

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

Nature

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

Endocrinology

Characterization of MCH-mediated obesity in mice

Am J Physiol Endocrinol Metab

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

J Clin Invest

Mice lacking melanin-concentrating hormone are hypophagic and lean

Nature

Molecular characterization of the melanin-concentrating-hormone receptor

Nature

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