A selective AMPA antagonist, LY293558, suppresses morphine withdrawal-induced activation of locus coeruleus neurons and behavioral signs of morphine withdrawal

Neuropsychopharmacology. 1996 Nov;15(5):497-505. doi: 10.1016/S0893-133X(96)00094-2.

Abstract

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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • Dose-Response Relationship, Drug
  • Electrophysiology
  • In Vitro Techniques
  • Isoquinolines / pharmacology
  • Isoquinolines / therapeutic use*
  • Locus Coeruleus / drug effects*
  • Locus Coeruleus / physiopathology
  • Male
  • Morphine / adverse effects*
  • Naltrexone
  • Narcotics / adverse effects*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / antagonists & inhibitors*
  • Substance Withdrawal Syndrome / prevention & control*
  • Tetrazoles / pharmacology
  • Tetrazoles / therapeutic use*

Substances

  • Isoquinolines
  • Narcotics
  • Receptors, AMPA
  • Tetrazoles
  • Naltrexone
  • tezampanel
  • Morphine