Abstract
The dopamine stabilizer (-)-OSU61612 dampens locomotion in rodents rendered hyperactive by exposure to a novel environment or treatment with amphetamine, but stimulates locomotion in habituated animals displaying low motor activity, tentatively exerting this profile by selectively blocking extrasynaptic D2 receptors. The major aim of the present study was to explore the possible usefulness of (-)-OSU61612 as an anti-aggressive drug. To this end, the effect of (-)-OSU61612 on isolation-induced aggression in male mice and estrous cycle-dependent aggression in female rats were studied using the resident intruder test; in addition, the possible influence of (-)-OSU61612 on sexual behavior in male mice and on elevated plus maze (EPM) performance in male rats were assessed. (-)-OSU61612 at doses influencing neither locomotion nor sexual activity reduced aggression in male mice. The effect was observed also in serotonin-depleted animals and is hence probably not caused by the antagonism of serotonin receptors displayed by the drug; refuting the possibility that it is due to 5-HT1B activation, it was also not counteracted by isamoltane. (-)-OSU61612 did not display the profile of an anxiogenic or anxiolytic drug in the EPM but caused a general reduction in activity that is well in line with the previous finding that it reduces exploratory behavior of non-habituated animals. In line with the observations in males, (-)-OSU61612 reduced estrus cycle-related aggression in female Wistar rats, a tentative animal model of premenstrual dysphoria. By stabilizing dopaminergic transmission, (-)-OSU61612 may prove useful as a well-tolerated treatment of various forms of aggression and irritability.