Elsevier

Physiology & Behavior

Volume 102, Issue 5, 28 March 2011, Pages 491-495
Physiology & Behavior

Brief communication
Central melanocortins modulate mesocorticolimbic activity and food seeking behavior in the rat

https://doi.org/10.1016/j.physbeh.2010.12.017Get rights and content

Abstract

The hypothalamic melanocortin system is known for its role in regulating energy homeostasis through it actions within hypothalamic brain centers. However, emerging evidence suggests that this system regulates addictive behaviors through signaling within mesolimbic neurons. Here, we hypothesized the melanocortin system modulates feeding behavior through its actions on mesolimbic neurons. In particular, we predicted that central administration of the melanocortin antagonist agouti-related peptide (AgRP) would activate midbrain dopamine neurons, increase mesolimbic dopamine turnover, and alter food seeking behaviors. We found that intraventricular administration of agouti-related peptide increased neuronal activation within midbrain dopamine neurons in addition to increasing dopamine turnover in the medial prefrontal cortex. Additionally, using the conditioned place preference paradigm to assay food seeking behavior, we report that central injection of agouti-related peptide attenuates the acquisition of a conditioned place preference for sucrose, but not high fat diet. These results suggest that the melanocortin system is capable of regulating mesocorticolimbic activity and food seeking behavior.

Introduction

The melanocortin system has been studied extensively for its role in the regulation of food intake. This system is unique in that it possesses both an endogenous agonist and an inverse agonist with opposite effects on feeding behavior. alpha-Melanocyte stimulating hormone (α-MSH) and agouti related peptide (AgRP) are the primary effector peptides of the melanocortin system. Increases in α-MSH serve to decrease food intake while increases in AgRP drive food consumption; under basal conditions the expression of each peptide is regulated by caloric status as they are downstream targets of the adiposity hormone leptin [16]. Traditionally, these peptides are thought to mediate their effects by binding specifically to the melanocortin-4 receptor (MC4R) within a distributed set of nuclei in the hypothalamus. However, emerging evidence suggests that this system is capable of mediating effects outside the hypothalamus, specifically within the mesolimbic system [2], [8]).

Separate from their expression in hypothalamic nuclei, melanocortin receptors (MC3R and MC4R) are also expressed in brain regions that regulate motivated behaviors [1], [2], [11]. Importantly, pharmacological studies have outlined functional roles for these receptors in the modulation of drug taking behavior. Specifically, antagonism of these receptors within nucleus accumbens inhibits operant responding for cocaine, while central agonism of this system augments amphetamine related behaviors [4], [8]. Moreover, the expression of the MC4R is increased in the striatum after repeated exposure to psychostimulants and mutant mice lacking this particular receptor fail to display a sensitized locomotor response to repeated cocaine administration [8]. In terms of food reward, central administration of AgRP increases neuronal activation within brain reward circuitry and augments operant responding for palatable food reinforcers [6], [7], [20] indicating that the nature by which melanocortins influence reward may differ depending on the particular reinforcer examined, i.e. drug vs. food. Taken together, these results suggest that the MC system is capable of influencing a variety of reward-related behaviors.

Here we hypothesized that the melanocortin antagonist AgRP would activate midbrain dopamine neurons and stimulate dopamine release within the mesolimbic system, in addition to modulating the conditioned place preference for food. In particular, we predicted that central injection of AgRP would increase c-Fos immunoreactivity within dopamine neurons in the ventral tegmental area and facilitate dopamine turnover in the nucleus accumbens (NAcc). We further predicted that antagonism of the MC system would enhance the conditioned place preference (CPP) for food. We found that central injection of AgRP activated dopamine containing neurons in the ventral tegmental area and increased dopamine turnover in the medial Prefrontal Cortex (mPFC). In addition, pharmacological administration of AgRP supported a CPP for high fat diet but attenuated CPP for sucrose. Collectively, these results suggest that melanocortin antagonists alter mesocortical dopamine neurochemistry, and modulate food seeking behavior.

Section snippets

Subjects

Thirty-two Long–Evans rats (Harlan, IN) weighing 200–250 g were housed individually in a vivarium with a 12:12 light/dark schedule. The temperature of the room was maintained at 25 °C. All animals had ad libitum access to food and water and were maintained on standard rodent chow. The temperature of the room was maintained at 25 °C. All animals had ad libitum access to food and water and were maintained on standard rodent chow. All procedures were approved by the Institutional Animal Care and Use

Immunohistochemistry

To determine if AgRP was sufficient to activate midbrain dopamine neurons we assessed the colocalization of c-Fos with tyrosine hydroxylase, the rate limiting enzyme for dopamine production, neurons. Compared to saline injected control rats, a 1 nmol dose of AgRP led to increased activation of TH neurons in the midbrain tissue (Fig. 1C and D) indicating that melanocortin antagonists are capable of eliciting neuronal activation within midbrain dopaminergic neurons. In addition, this dose of AgRP

Discussion

The goal of the current study was to determine if the melanocortin system was capable of activating midbrain dopamine neurons and modulating mesolimbic dopamine flux. A separate goal was to determine the ability of AgRP to affect food seeking behavior using the conditioned place preference procedure. From these efforts several significant findings emerged: 1) Central administration of AgRP enhanced neuronal activation within dopaminergic neurons in the ventral tegmental area; 2) AgRP

References (22)

  • K. Mountjoy et al.

    Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain

    Mol Endocrinol

    (1994)
  • Cited by (0)

    View full text