Melanocortin 3 receptors (MC3R) and melanocortin 4 receptors (MC4R) are vital in regulating a variety of functions across many species. For example, the dysregulation of these receptors results in obesity and dysfunction in sexual behaviors. Only a handful of studies have mapped the expression of MC3R and MC4R mRNA across the central nervous system, with the primary focus on mice and rats. Because Syrian hamsters are valuable models for functions regulated by melanocortin receptors, our current study maps the distribution of MC3R and MC4R mRNA in the Syrian hamster telencephalon, diencephalon, and midbrain using RNAscope. We found that the expression of MC3R mRNA was lowest in the telencephalon and greatest in the diencephalon, whereas the expression of MC4R mRNA was greatest in the midbrain. A comparison of these findings to previous studies found that MC3R and MC4R expression is similar in some brain regions across species and divergent in others. In addition, our study identifies novel brain regions for the expression of MC3Rs and MC4Rs, and identifies cells that co-express bothMC3 and MC4 receptors within certain brain regions.
Like many social behaviors, aggression can be rewarding, leading to behavioral plasticity. One outcome of reward-induced aggression is the long-term increase in the speed in which future aggression-based encounters is initiated. This form of aggression impacts dendritic structure and excitatory synaptic neurotransmission in the nucleus accumbens, a brain region well known to regulate motivated behaviors. Yet, little is known about the intracellular signaling mechanisms that drive these structural/functional changes and long-term changes in aggressive behavior. This study set out to further elucidate the intracellular signaling mechanisms regulating the plasticity in neurophysiology and behavior that underlie the rewarding consequences of aggressive interactions. Female Syrian hamsters experienced zero, two or five aggressive interactions and the phosphorylation of proteins in reward-associated regions was analyzed. We report that aggressive interactions result in a transient increase in the phosphorylation of extracellular-signal related kinase 1/2 (ERK1/2) in the nucleus accumbens. We also report that aggressive interactions result in a transient decrease in the phosphorylation of mammalian target of rapamycin (mTOR) in the medial prefrontal cortex, a major input structure to the nucleus accumbens. Thus, this study identifies ERK1/2 and mTOR as potential signaling pathways for regulating the long-term rewarding consequences of aggressive interactions. Furthermore, the recruitment profile of the ERK1/2 and the mTOR pathways are distinct in different brain regions.
Hypoactive sexual desire disorder (HSDD) in women is a condition of low sexual desire that develops over time. Sexual desire normally diminishes over long-term relationships, but is also negatively affected by a demanding lifestyle, poor self-esteem and body image, and loss of intimacy in a relationship. HSDD elevates to a disorder when it is a concern for the woman, arising from conflict with a partner who is interested in a greater frequency of sexual interaction. Two drugs have been marketed (Addyi and Vyleesi) to treat HSDD. Neither drug was originally developed for this purpose, nor is either drug particularly effective. The lack of rational development of drugs to treat sexual disorders in women is due to the mistaken belief that components of female sexuality, such as sexual desire, cannot be effectively modeled in animals. To the contrary, sexual interest, desire, arousal, and reward are measurable aspects of sexual behavior in female rodents. Going forward, basic research using these pre-clinical models should be the starting point for drug development. At the same time, it is not clear that drug development represents the primary therapeutic approach to the problem, with behavioral therapies providing good options for first line of treatments for HSDD.
Introduction Low sexual desire is a commonly reported and often distressing form of sexual dysfunction in women. Characterized by diminished interest in sex, disinclination to initiate sex, and a loss of pleasure during sex, disorders of sexual desire among women are not only poorly understood from a psychological perspective, but also in terms of their underlying neurobiology. The drug bremelanotide, trade name Vyleesi, was approved by the FDA in 2019 to treat hypoactive sexual desire disorder in women. The drug is a synthetic analogue of the melanocortin receptor (MCR) agonist alpha-MSH and thus thought to bind to the melanocortin-4 receptor (MC4R) in the brain. However, despite its FDA approval, few preclinical studies or clinical trials have been performed on the drug. Objective We attempted to elucidate bremelanotide’s central nervous system effects in an established rodent model of female sexual behavior. Methods Female Syrian hamsters underwent 0, 2 or 5 weeks of sexual conditioning in the conditioned place preference apparatus, a validated model that is designed to test the rewarding properties of sexual behavior. Some hamsters that were conditioned for 2 weeks were also given a subcutaneous injection of bremelanotide. After the sexual conditioning experiment, brains were collected for assessment of MC4R expression in the striatum. mRNA expression of dopamine-1 and 2 receptors and MC4R were carried out using Syrian hamster customized RNAscope probes. Results Analysis of behavior data indicated the longer (5-week) sexual conditioning period was most effective for increasing responses indicative of reward, though the shorter (2-week) period also increased reward. However, neither the low dose nor high dose of bremelanotide increased reward responding as compared to control hamsters. Further, no brain changes in MC4R expression in the striatum were detected as a function of either sexual experience or bremelanotide treatment. MC4R was not co-expressed with dopamine-1 or dopamine-2 receptors in the nucleus accumbens or dorsal striatum. Conclusions Bremelanotide did not increase responding indicative of reward derived from sex in the female Syrian hamster model. Given that MC4R expression was unaffected by sexual experience and/or bremelanotide, our findings did not provide evidence that the drug acts via an MC4R-related mechanism in the central nervous system. MC4R was also not co-expressed with dopamine-1 or 2 receptors, suggesting the MC4R may instead be expressed by interneurons in the striatum. Despite our lack of evidence to support bremelanotide’s efficacy in animals, limitations of the rodent model of female sex behavior include the obvious psychosocial aspects of human sexuality that cannot be replicated. Further research is warranted to clarify bremelanotide’s mechanism of action. Disclosure No
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