The selective iGluR1-4 (AMPA) antagonist LY300168 attenuates morphine-withdrawal-induced activation of locus coeruleus neurons and behavioural signs of morphine withdrawal.
Previously, we have shown that the AMPA (iGluR1-4) antagonist LY293558 attenuates the morphine-withdrawal-induced activation of locus coeruleus neurons and behavioral signs of morphine withdrawal. However, LY293558 has since been shown to also have affinity for one subtype of kainate receptor (iGluR5). In this study, we examined the effects of a selective antagonist of iGluR1-4 receptors, LY300168 (GYKI 53655), and a selective antagonist of iGluR5 receptors, LY382884, on the morphine-withdrawal-induced activation of locus coeruleus neurons and behavioral signs of morphine withdrawal. In in vivo recordings from anesthetized rats, pretreatment with LY300168 (0.3-3.0 mg/kg, s.c.), but not LY382884 (at a dose known to have central effects; 100 mg/kg, s.c.) attenuated the morphine-withdrawal-induced activation of LC neurons. In unanesthetized, morphine-dependent rats, pretreatment with LY300168 (0.3-3.0 mg/kg, s.c.), but not LY382884 (100 mg/kg, s.c.), suppressed the severity and occurrence of naltrexone-precipitated morphine-withdrawal signs. These results indicate iGluR1-4 (AMPA) receptors, but not iGluR5 receptors, play an important role the morphine-withdrawal-induced activation of LC neurons and a subset of behavioral signs of morphine withdrawal. In addition, selective AMPA antagonists may have therapeutic effects in man for the treatment of withdrawal from opiates and other drugs of abuse.
Rasmussen
Kurt
K
Neuroscience Research, Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA. rasmussen_kurt@lilly.com
Vandergriff
Jim
J
D000494:Allosteric Regulation; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001569:Benzodiazepines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008125:Locus Coeruleus / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D009020:Morphine / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology / Q000517:prevention & control* / Q000523:psychology
D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; C400802:LY382884; D018091:Receptors, AMPA; D001569:Benzodiazepines; C079692:GYKI 53655; D009020:Morphine