Identification of a pheromone that increases anxiety in rats

Abstract

Chemical communication plays an important role in the social lives of various mammalian species. Some of these chemicals are called pheromones. Rats release a specific odor into the air when stressed. This stress-related odor increases the anxiety levels of other rats; therefore, it is possible that the anxiety-causing molecules are present in the stress-related odorants. Here, we have tried to identify the responsible molecules by using the acoustic startle reflex as a bioassay system to detect anxiogenic activity. After successive fractionation of the stress-related odor, we detected 4-methylpentanal and hexanal in the final fraction that still possessed anxiogenic properties. Using synthetic molecules, we found that minute amounts of the binary mixture, but not either molecule separately, increased anxiety in rats. Furthermore, we determined that the mixture increased a specific type of anxiety and evoked anxiety-related behavioral responses in an experimental model that was different from the acoustic startle reflex. Analyses of neural mechanisms proposed that the neural circuit related to anxiety was only activated when the two molecules were simultaneously perceived by two olfactory systems. We concluded that the mixture is a pheromone that increases anxiety in rats. To our knowledge, this is the first study identifying a rat pheromone. Our results could aid further research on rat pheromones, which would enhance our understanding of chemical communication in mammals.stress-related odor | alarm pheromone | acoustic startle reflex | anxiety | rat C hemical communication plays an important role in the social lives of various mammalian species. Some of these chemicals are called "pheromones." Because the term pheromone was coined and defined based on findings in insects (1), there is still a debate as to whether the original definition can be applied to mammals (2). Researchers have proposed revised definitions by modifying the original definition and/or specifying additional requirements (3-6). On the basis of the original and revised definitions, we set a working definition of pheromone within this study as (i) substances that are secreted to the outside by an individual and received by a second individual of the same species, in which they cause a specific reaction; (ii) substances that are effective in minute amounts; (iii) substances that are released from living individuals; and (iv) substances that mediate communication for an evolutionarily adaptive function.Rats release a specific odor into the air when stressed (7). This stress-related odor increases anxiety levels (8, 9) and induces a variety of anxiety-related responses depending on their situation with other rats (9-18). Rats respond to their own stressrelated odor in a similar manner to odor released from the other rats, suggesting that the odor has general effects (10,19). In addition, the stress-related odor appears to be effective in minute amounts (20,21). Therefore, the molecules responsible for increasing anxiety levels should exist in the...

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