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.
Highlights
For a number of psychiatric conditions, symptoms such as violent aggression, anger and irritability contribute considerably to the burden of disease
The effect was observed in serotonin-depleted animals and is 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 not counteracted by isamoltane. ( − )-OSU61612 did not display the profile of an anxiogenic or anxiolytic drug in the elevated plus maze (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
We report that a dopamine stabilizer, (− )-OSU6162, elicits a dosedependent reduction of aggressive behavior at doses not interfering with the other aspects of social behavior, general locomotor activity or sexual behavior
Summary
For a number of psychiatric conditions, symptoms such as violent aggression, anger and irritability contribute considerably to the burden of disease. D2 antagonists exert an anti-aggressive effect in rodents,[8] which is well in line with the observation that both firstand second-generation antipsychotics may dampen aggression in various psychiatric conditions.[3] The cumbersome side effects marring both traditional and atypical antipsychotic drugs, make these drugs far from optimal for this purpose. The phenylpiperidine ( − )-OSU61612, displaying affinity but no or weak intrinsic activity for dopaminergic D2 receptors in vivo,[9] modulates D2 receptor-influenced behavior differently as compared with all previously known D2 antagonists.[10,11] ( − )-OSU61612 mimics the effect of D2 antagonists by dampening locomotion in animals displaying hyperactivity after having been placed in a novel environment[11,12] or treated with amphetamine,[9,12] it increases locomotion in rats with low activity; because of this profile, it has been named a dopamine stabilizer.[9,13,14] Though displaying an antipsychotic-like profile in various tentative animal models of schizophrenia,[12,15] unlike most D2-blocking antipsychotic drugs ( − )-OSU61612 does not cause catalepsy even at high doses in rodents;[12] in line with this, early clinical experience suggests ( − )-OSU61612 to be largely devoid of the extrapyramidal side effects characterizing most D2-blocking antipsychotics.[16]
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