Heightened aggressive behavior during morphine withdrawal: effects of d-amphetamine.

The morphine withdrawal syndrome is composed of profound short- and long-term changes in autonomic, somato-motor and affective functions. In mice, morphine withdrawal produces heightened aggressive behavior and alterations in motor behavior; however, it is unclear whether these changes in behavior occur in unison and are dependent on a common mechanism or occur independently. In order to characterize the morphine withdrawal syndrome in mice, male Swiss-Webster mice were housed with female partners for 3-4 weeks before being implanted subcutaneously with morphine or placebo pellets. The pellets were removed 72 h after implantation and behavioral measurements were conducted 5, 48 and 96 h after pellet removal. During these tests, mice received d-amphetamine (0.3-10 mg/kg) or saline after which they were assessed for changes in motor behavior and for changes in aggressive behavior while confronting a group-housed male "intruder". In morphine-withdrawn mice, frequency of attack behavior was increased by approximately 30% and this effect persisted for at least 4 days. In contrast, explosive jumping was increased and walking and rearing were greatly decreased at the onset of the withdrawal period but declined within the first 24 h and returned to control levels within 48 h of pellet removal. d-Amphetamine maintained the elevated level of aggressive behavior and sharply increased locomotion in morphine-withdrawn mice; in placebo-pelleted mice, d-amphetamine dose-dependently decreased aggressive behaviors while increasing locomotion. The differential time course and the differential modification by d-amphetamine suggest that heightened aggressive behavior is a long-lasting consequence of morphine-withdrawal based on separate mechanisms than the short-lived alterations in motor activity.