NMDA receptor antagonists suppress behaviors but not norepinephrine turnover or locus coeruleus unit activity induced by opiate withdrawal.
Pretreatment with the non-competitive NMDA (N-methyl-D-aspartate) antagonist MK801 (0.5, 1.0 mg/kg, s.c.) suppressed the behavioral signs of withdrawal in morphine-dependent rats. However, the same doses of MK801 that suppressed morphine withdrawal also simultaneously produced phencyclidine (PCP)-like behaviors. Pretreatment with the competitive NMDA antagonist LY274614 (25, 50, 100 mg/kg i.p.) also suppressed the behavioral signs of withdrawal in morphine-dependent rats but did not produce PCP-like behavioral effects. Single unit recordings were made from noradrenergic neurons in the locus coeruleus (LC) and, at doses that suppressed morphine withdrawal behaviors, neither MK801 nor LY274614 blocked the withdrawal-induced activation of LC neurons. Biochemical analysis indicated that, at the same behaviorally relevant doses, neither MK801 nor LY274614 blocked the withdrawal-induced increase in norepinephrine turnover in the hippocampus, cerebral cortex, or hypothalamus. These results indicate that NMDA antagonists attenuate the behavioral signs of morphine withdrawal without blocking the withdrawal-induced increase in norepinephrine turnover or the withdrawal-induced increase in LC unit activity. In addition, non-competitive NMDA antagonists, like MK801, may not be useful to alleviate opiate withdrawal symptoms in man because of their PCP-like side effects. However, competitive NMDA antagonists, like LY274614, could be of great benefit for alleviating opiate withdrawal symptoms in man.
Rasmussen
K
K
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285.
Fuller
R W
RW
Stockton
M E
ME
Perry
K W
KW
Swinford
R M
RM
Ornstein
P L
PL
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004594:Electrophysiology; D007546:Isoquinolines; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000523:psychology*
D007546:Isoquinolines; D016194:Receptors, N-Methyl-D-Aspartate; C070935:LY 274614; D009271:Naltrexone; D016291:Dizocilpine Maleate; D009020:Morphine; D009638:Norepinephrine