Long-lasting pseudo-social aggressive behavior in opiate-withdrawn mice

Poor sociability and aggressive behavior are major clinical features of opiate use disorders that may contribute to the establishment and maintenance of these harmful diseases. The present study investigated the long-term effects of chronic morphine administration and withdrawal upon social and aggressive behavior as well as the interrelationship between these two behaviors. Thus, social behavior was measured in C57BL/6J male mice 7, 21, 35 and 49 days after cessation of escalating morphine doses (20-100 mg/kg, i.p.) administered during 6 consecutive days, using the three-chamber task for sociability (i.e., preference for an unfamiliar conspecific vs. an object) and social novelty preference (i.e., preference for a novel vs. a familiar conspecific). Moreover, aggressive biting behavior towards an unfamiliar conspecific was assessed throughout the three-chamber tests. Opiate withdrawal increased both social approach and aggressive biting behavior. Moreover, in morphine-withdrawn, but not in control, mice social approach and aggressive behavior followed a similar time-course and positively correlated one with each other, suggesting that social interest was mainly driven by aggressiveness. Aggressive biting behavior was still elevated 49 days after the last morphine administration, revealing that opiate withdrawal is followed by long-lasting aggressiveness. Throughout, opiate withdrawal did not affect social novelty preference, ruling out a role for olfactory or social discrimination dysfunction in the elevated social approach and aggressive behavior. The present findings of very long-lasting aggressive behavior and aggression-driven social approach in opiate-withdrawn mice might help understanding the behavioral and brain underpinnings of poor sociability and aggressiveness commonly observed in opiate use disorders patients.