The melanin-concentrating hormone system modulates cocaine reward

Abstract

Drug addiction is mediated by complex neuronal processes that converge on the shell of the nucleus accumbens (NAcSh). The NAcSh receives inputs from the lateral hypothalamus (LH), where selfstimulation can be induced. Melanin-concentrating hormone (MCH) is produced mainly in the LH, and its receptor (MCH1R) is highly expressed in the NAcSh. We found that, in the NAcSh, MCH1R is coexpressed with dopamine receptors (D1R and D2R), and that MCH increases spike firing when both D1R and D2R are activated. Also, injecting MCH potentiates cocaine-induced hyperactivity in mice. Mice lacking MCH1R exhibit decreased cocaine-induced conditioned place preference, as well as cocaine sensitization. Using a specific MCH1R antagonist, we further show that acute blockade of the MCH system not only reduces cocaine self-administration, but also attenuates cue-and cocaine-induced reinstatement. Thus, the MCH system has an important modulatory role in cocaine reward and reinforcement by potentiating the dopaminergic system in the NAcSh, which may provide a new rationale for treating cocaine addiction.T he shell of the nucleus accumbens (NAcSh) is known to be an important center for reward and motivation. It is a major terminal area of the mesolimbic dopamingergic system, which projects from the ventral tegmental area (VTA) (1). The NAcSh neurons express both dopamine D1 and D2 receptors, which have opposite effects on cAMP-dependent signaling; however, motivated behaviors require concomitant D1 and D2 receptor signaling in the NAcSh (2). The NAcSh receives inputs from different brain areas, in particular, from the lateral hypothalamus (LH) (3). The importance of the LH in reward and motivation has been shown by Olds (4), who discovered that electrical activation of the LH induced an extraordinarily intense self-stimulation response in rats. However, the transmitter(s) responsible for this action have not been established definitively. We now know of 2 neuropeptides that are uniquely synthesized in the LH: the orexins/hypocretins (5), and melanin-concentrating hormone (MCH) (6-8). The orexin/ hypocretin neurons do not project prominently to the NAcSh, whereas the MCH neurons do (9). This data suggested to us that the MCH system may regulate the activities of the NAcSh neurons to influence reward.MCH is a cyclic, 19-amino acid peptide originally isolated from salmon pituitary as a melanophore-concentrating factor (10). It is also present in rats and humans (11,12), where it is viewed as important in regulating nutritional homeostasis (8, 13). In mammals, MCH is expressed predominantly centrally, and occurs only in 2 nuclei: the perikarya of the LH area (LHA), and the zona incerta (ZI). However, MCH fibers project in many areas throughout the CNS (6, 9), indicating that the MCH system may have a broad range of physiological roles. In rodents, MCH is known to interact with one G protein-coupled receptor, MCH1R (14-18). MCH1R is expressed in many brain regions (9), and the NAcSh has one of the highest MCH1R expression levels. Indeed, the ...

A Confirmed Case of Agranulocytosis after Use of Cocaine Contaminated with Levamisole

“…Since adding an inert ingredient to illicit cocaine prior to shipment into the USA makes smuggling more difficult, the possibility that levamisole is an effect modifier must be carefully considered. Recent research shows that cocaine addiction is modulated by the dopamine-and melaninconcentrating hormone systems of the mesolimbic system and nucleus accumbens of the brain [16]. In animal models, levamisole increases dopamine levels in the hypothalamus, striatum, and midbrain [17].…”

Dopamine Acts as a Partial Agonist for 2A Adrenoceptor in Melanin-Concentrating Hormone Neurons

“…MCH promotes positive energy balance by increasing food intake (Qu et al, 1996;Shimada et al, 1998;Ludwig et al, 2001) and sleep (Verret et al, 2003;Willie et al, 2008), while inhibiting metabolism and locomotion (Shimada et al, 1998;Marsh et al, 2002). MCH also modulates behavioral responses to palatable food and drugs of abuse by its action in the nucleus accumbens (Borowsky et al, 2002;Smith et al, 2005;Chung et al, 2009). Involvement of MCH in emotion and mood disorders has been put forward by studies demonstrating that MCH receptor antagonists exert anxiolytic and antidepressant effects in animal models (Borowsky et al, 2002;Georgescu et al, 2005).…”

Pmchexpression during early development is critical for normal energy homeostasis

“…MCH1R is particularly enriched in the nucleus accumbens shell (33,47,56), thus forming a potential hypothalamiclimbic circuit modulating the hedonic, or rewarding, aspects of feeding (16,47). Recently, it was indeed shown that the MCH system affects motivation for feeding or drugs of abuse (9,42). Rodents only express MCH1R, whereas humans also express a second MCH receptor, MCH2R (54).…”