Ionotropic glutamate receptor antagonists modulate cue-induced reinstatement of ethanol-seeking behavior.
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.
Bäckström
Pia
P
Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland.
Hyytiä
Petri
P
D000428:Alcohol Drinking / Q000188:drug therapy* / Q000523:psychology; D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy* / Q000523:psychology; D003463:Cues; D000431:Ethanol / Q000008:administration & dosage*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology; D008297:Male; D051381:Rats; D020318:Rats, Long-Evans; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D017470:Receptors, Glutamate / Q000502:physiology
D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate; D000431:Ethanol