Effects of the NMDA receptor channel blockers memantine and MRZ 2/579 on morphine withdrawal-facilitated aggression in mice.
BACKGROUND
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. Antagonists acting at the NMDA receptor are known to attenuate the expression of morphine withdrawal syndrome in laboratory animals.


OBJECTIVE
The present study aimed to evaluate the effects of low-affinity NMDA receptor channel blockers (memantine and MRZ 2/579) on aggression facilitated by morphine withdrawal in mice.


METHODS
Significant increases in aggressive behavior were observed 48 h after repeated morphine administration (8 days, b.i.d., 10-80 mg/kg, s.c.) was discontinued. Separate groups of mice were treated intraperitoneally 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 injection.


RESULTS
Both compounds dose-dependently reduced the expression of aggressive behavior while having no significant effect upon the intensity of non-aggressive social contacts. Memantine significantly diminished the occurrence of all recorded components of aggressive behavior (attacks/bites, threats, tail rattling) while MRZ 2/579 affected mainly the appetitive events of aggressive bursts (threats, tail rattling). For both compounds, anti-aggressive effects occurred at dose levels that did not produce motor impairment 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 due to specific interaction with morphine withdrawal-triggered processes.
Sukhotina
I A
IA
Laboratory of Behavioral Pharmacology, Institute of Pharmacology, Pavlov Medical University, St. Petersburg, Russia.
Bespalov
A Y
AY
D000374:Aggression / Q000187:drug effects*; D000818:Animals; D003517:Cyclopentanes / Q000494:pharmacology* / Q000627:therapeutic use; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008559:Memantine / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D009020:Morphine / Q000009:adverse effects; D009294:Narcotics / Q000009:adverse effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology; D012919:Social Behavior; D013375:Substance Withdrawal Syndrome / Q000150:complications* / Q000188:drug therapy
D003517:Cyclopentanes; D018691:Excitatory Amino Acid Antagonists; D009294:Narcotics; D016194:Receptors, N-Methyl-D-Aspartate; D009020:Morphine; C114144:neramexane; D008559:Memantine