A selective AMPA antagonist, LY293558, suppresses morphine withdrawal-induced activation of locus coeruleus neurons and behavioral signs of morphine withdrawal.
The glutamate receptor subtype that mediates the morphine withdrawal-induced activation of locus coeruleus (LC) neurons was examined in this study using in vitro and in vivo single-unit electrophysiologic recordings. For LC neurons recorded in vitro in rat brain slices, the selective alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) antagonist, LY293558, showed a greater than 10-fold selectivity for inhibiting the excitatory effects of AMPA vs kainate, and a greater than 30-fold selectivity for inhibiting the excitatory effects of AMPA vs NMDA. LY293558 also greatly reduced the response of LC neurons to glutamate in a concentration-dependent manner. In in vivo recordings in anesthetized rats, pretreatment with LY293558 (0.1 to 10 mg/kg, i.p.) dose dependently suppressed the morphine withdrawal-induced activation of LC neurons. In unanesthetized, morphine-dependent animals, pretreatment with LY293558 (1 to 30 mg/kg, i.p.) dose dependently suppressed naltrexone-precipitated morphine withdrawal signs. These results indicate: (1) AMPA receptors mediate a large component of the excitatory effects of glutamate on LC neurons; (2) activation of AMPA receptors plays an important role in the morphine withdrawal-induced activation of LC neurons; (3) AMPA antagonists can suppress many signs of morphine withdrawal in awake animals; and (4) AMPA antagonists may have therapeutic effects in humans for the treatment of opiate withdrawal.
Rasmussen
K
K
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, Indiana 46285, USA.
Kendrick
W T
WT
Kogan
J H
JH
Aghajanian
G K
GK
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use*; D008125:Locus Coeruleus / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D009020:Morphine / Q000009:adverse effects*; D009271:Naltrexone; D009294:Narcotics / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control*; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*
D007546:Isoquinolines; D009294:Narcotics; D018091:Receptors, AMPA; D013777:Tetrazoles; D009271:Naltrexone; C082309:tezampanel; D009020:Morphine