Brief communicationCentral melanocortins modulate mesocorticolimbic activity and food seeking behavior in the rat
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)
- et al.
Brain melanocortin receptors: from cloning to function
Peptides
(1997) - et al.
The melanocortin receptor agonist MTII augments the rewarding effects of amphetamines in ad-libitum fed and food restricted rats
Psychopharmacology
(2002)et al.Dopamine terminals synapse on callosal projection neurons in the rat prefrontal cortex
J Comp Neurol
(2000)et al.The role of orexin-A in food motivation, reward-based feeding behavior and food-induced neuronal activation in rats
Neuroscience
(2010) - et al.
The MC4 receptor mediates α-MSH induced release of nucleus accumbens dopamine
NeuroReport
(2001) - et al.
Morphine down regulates melanocortin-4 receptor expression in brain regions that mediate opiate addiction
Mol Pharmacol
(1996)et al.Molecular and behavioral interactions between central melanocortins and cocaine
J Pharmacol Exp Ther
(2003)et al.Role of lateral hypothalamic orexin neurons in reward processing and addiction
Neuropharmacology
(2009)Balcita-Pedicino JJ, Sesack SR. Orexin axons in the rat ventral tegmental area synapse infrequent.... - et al.
Differential influence of associative and nonassociative learning mechanism on the responsiveness of prefrontal and accumbal dopamine transmission to food stimuli in rats fed ad libitum
J Neurosci
(1997) - et al.
Associative learning mediates dynamic shifts in dopamine signaling in the nucleus accumbens
Nat Neurosci
(2007) - et al.
Immediate and prolonged patterns of Agouti related peptide-(83–132) induced c-fos activation in hypothalamic and extrahypothalamic sites
Endocrinology
(2001) - et al.
Opioid receptor involvement in the effect of AgRP-(83–132) on food intake and food selection
Am J Physiol Regul Integr Comp Physiol
(2001) - et al.
Blockade of melanocortin transmission inhibits cocaine reward
Eur J Neurosci
(2005) - et al.
Identification of wake-active dopaminergic neurons in the ventral periaqueductal grey matter
J Neurosci
(2006)