Effects of the NMDA receptor channel blockers memantine and MRZ 2/579 on morphine withdrawal-facilitated aggression in mice

Rationale: Opioid withdrawal is known to facilitate aggressive behavior in laboratory rodents. Aggression develops as the somatic signs disappear and thus may reflect protracted withdrawal-related behavioral alterations. Anta gonists acting at the NMDA receptor are known to attenuate the expression o f morphine withdrawal syndrome in laboratory animals. Objective: The presen t study aimed to evaluate the effects of low-affinity NMDA receptor channel blockers (memantine and MRZ 2/579) on aggression facilitated by morphine w ithdrawal in mice. Methods: Significant increases in aggressive behavior we re observed 48 h after repeated morphine administration (8 days, b.i.d., 10 -80 mg/kg, SC) was discontinued. Separate groups of mice were treated intra peritoneally with vehicles or different doses of memantine (1, 3, 10 or 30 mg/kg) or MRZ 2/579 (1, 3 or 10 mg/kg) 48 h after the last morphine injecti on. Results: Both compounds dose-dependently reduced the expression of aggr essive behavior while having no significant effect upon the intensity of no n-aggressive social contacts. Memantine significantly diminished the occurr ence of all recorded components of aggressive behavior (attacks/bites, thre ats, tail rattling) while MRZ 2/579 affected mainly the appetitive events o f aggressive bursts (threats, tail rattling). For both compounds, anti-aggr essive effects occurred at dose levels that did not produce motor impairmen t in the Rotarod test. Conclusions: Taken together with the evidence on the lack of selective anti-aggressive effects of these drugs in morphine-naive mice, attenuation of the aggression observed in the present study may be d ue to specific interaction with morphine withdrawal-triggered processes.