Melanocortin receptor agonist melanotan-II microinjected in the nucleus accumbens decreases appetitive and consumptive responding for food.
This study investigated the role of melanocortin signaling in the nucleus accumbens (NAcc) on food intake and motivation to eat in mice. Male C57BL/6J mice received bilateral microinjections of melanotan-II (MT-II), a melanocortin receptor 3/4 agonist, directly into the NAcc, and researchers measured effects on food consumption and operant responding for food. The study found that MT-II microinjected into the NAcc significantly reduced both the amount of food consumed (measured in home cage settings) and appetitive responding (measured by operant self-administration tasks requiring effort to obtain food). Importantly, these effects appeared to occur without inducing conditioned taste avoidance—suggesting the reductions were not due to nausea or aversion—and without measurable changes in metabolic rate. The authors concluded that melanocortin signaling in the NAcc may selectively regulate appetite and satiety independent of metabolism or aversive side effects. Key limitations include that this was an animal-only study conducted exclusively in male mice of a single inbred strain, limiting generalizability to other sexes, species, or humans. The microinjection approach is also not clinically translatable in its current form.
Why this grade: The study was conducted entirely in male C57BL/6J mice using intracranial microinjections, with no human subjects or clinical data, providing no direct evidence of efficacy or safety in humans.
Rationale Obesity is a major health problem worldwide. An understanding of the factors that drive feeding behaviors is key to the development of pharmaceuticals to decrease appetite and consumption. Proopiomelanocortin (POMC), the melanocortin peptide precursor, is essential in the regulation of body weight and ingestive behaviors. Deletion of POMC or impairment of melanocortin signaling in the brain results in hyperphagic obesity. Neurons in the hypothalamic arcuate nucleus produce POMC and project to many areas including the nucleus accumbens (NAcc), which is well established in the rewarding and reinforcing effects of both food and drugs of abuse. Objective These studies sought to determine the role of melanocortins in the NAcc on consumption of and motivation to obtain access to standard rodent chow. Methods Male, C57BL/6J mice were microinjected bilaterally into the NAcc (100 nl/side) with the melanocortin receptor 3/4 agonist melanotan-II (MT-II; 0.1, 0.3, and 1 nmol), and ingestive behaviors were examined in both home cage and operant food self-administration experiments. In addition, the ability of MT-II in the NAcc to produce aversive properties or affect metabolic rate were tested. Results MT-II injected into the NAcc significantly decreased consumption in both home cage and operant paradigms, and furthermore decreased appetitive responding to gain access to food. There was no development of conditioned taste avoidance or change in metabolic parameters following anorexic doses of MT-II. Conclusions MT-II in the NAcc decreased both the motivation to eat and the amount of food consumed without inducing an aversive state or affecting metabolic rate, suggesting a role for melanocortin signaling in the NAcc that is selective for appetite and satiety without affecting metabolism or producing an aversive state.
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