AMPA antagonist LY293558 blocks the development, without blocking the expression, of behavioral sensitization to morphine.
Morphine (3.0 mg/kg, s.c.) stimulates locomotor activity in rats, and this effect sensitizes with repeated intermittent treatment. We examined the ability of the AMPA antagonist LY293558, administered systemically over a range of doses (0.1-3.0 mg/kg), to alter morphine sensitization. Pretreatment with 3.0 mg/kg LY293558 attenuated the acute (session 1) locomotor-stimulating actions of morphine, whereas 1.0, 0.3, and 0.1 mg/kg were without effect. No sensitization was observed after repeated morphine treatment (3.0 mg/kg, s.c., every other day for 9 days) when morphine injections were preceded by 0.3, 1.0, or 3.0 mg/kg LY293558, whereas significant sensitization was observed when morphine injections were preceded by vehicle or 0.1 mg/kg of the antagonist. When all rats were challenged with morphine (3.0 mg/kg, s.c.) alone on day 11, the locomotor activity of rats previously exposed to LY293558 at 3.0, 1.0, or 0.3 mg/kg--but not at 0.1 mg/kg--was significantly lower than that of rats previously given morphine preceded by vehicle. On day 13, pretreatment with 1.0 mg/kg LY293558 failed to alter preestablished morphine sensitization in rats previously pretreated with vehicle. These data indicate that LY293558 blocks the development but not the expression of morphine sensitization, confirming a role for AMPA receptors in the initiation of neurobiological adaptations that occur with chronic morphine treatment.
Laboratory of Molecular Psychiatry, Yale University School of Medicine, Connecticut Mental Health Center, New Haven 06508, USA.
W A
WA
Carlezon
K
K
Rasmussen
E J
EJ
Nestler
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009294:Narcotics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D013777:Tetrazoles / Q000494:pharmacology*
D007546:Isoquinolines; D009294:Narcotics; D018091:Receptors, AMPA; D013777:Tetrazoles; C082309:tezampanel; D009020:Morphine