Ionotropic glutamate receptor antagonists modulate cue-induced reinstatement of ethanol-seeking behavior

Alcohol Clin Exp Res. 2004 Apr;28(4):558-65. doi: 10.1097/01.alc.0000122101.13164.21.


Background: Glutamatergic neurotransmission has been implicated in drug-environment conditioning, but little is known about the role of glutamate in alcohol seeking maintained by alcohol-associated cues. Therefore, we examined the effects of ionotropic glutamate receptor antagonists on cue-induced ethanol-seeking behavior in the extinction/reinstatement model.

Methods: Rats were trained to orally self-administer ethanol (10% w/v) and a nonrewarding (80 microM) quinine solution on randomly alternating days. Ethanol and quinine availability were signaled by olfactory discriminative stimuli (S+/S-). In addition, ethanol delivery was accompanied by a light stimulus (CS+) and quinine delivery by an auditory stimulus (CS-). Thereafter, rats were subjected to extinction training during which responding had no programmed consequences. Reinstatement of responding was tested under three conditions: in the presence of the S-/CS-, S+/CS+, and S+/CS+ together with a small (0.2 ml) response-contingent oral ethanol dose at the beginning of the reinstatement session (S+/CS+/priming). We examined the effects of the noncompetitive NMDA receptor antagonist MK-801 (0, 0.05, 0.15 mg/kg intraperitoneally), the competitive NMDA antagonist CGP39551 (0, 5, 10 mg/kg intraperitoneally), the NMDA/glycine receptor antagonist L-701,324 (0, 2, 4 mg/kg intraperitoneally), the AMPA/kainate receptor antagonist CNQX (0, 0.5, 1.5 mg/kg intraperitoneally), and the opioid receptor antagonist naltrexone (0, 0.3, 1 mg/kg subcutaneously) on ethanol seeking under the S+/CS+/priming condition.

Results: Presentation of the S+/CS+ stimulus condition reinstated extinguished responding, whereas presentation of the S-/CS- condition did not. Response-contingent ethanol priming enhanced reinstatement further. Under these reinstatement conditions, L-701,324, CNQX, and naltrexone inhibited ethanol-seeking behavior significantly. In contrast, MK-801 and CGP39551 failed to affect reinstated responding.

Conclusions: These results show that glutamate antagonism suppresses ethanol-seeking behavior induced by ethanol-paired stimuli. Furthermore, the data suggest that ionotropic glutamate receptors may have differential roles in mediation of this behavior.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Drinking / drug therapy*
  • Alcohol Drinking / psychology
  • Animals
  • Behavior, Addictive / drug therapy*
  • Behavior, Addictive / psychology
  • Cues*
  • Ethanol / administration & dosage*
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Amino Acid Antagonists / therapeutic use*
  • Extinction, Psychological / drug effects
  • Extinction, Psychological / physiology
  • Male
  • Rats
  • Rats, Long-Evans
  • Reaction Time / drug effects
  • Reaction Time / physiology
  • Receptors, Glutamate / physiology


  • Excitatory Amino Acid Antagonists
  • Receptors, Glutamate
  • Ethanol