Ethanol-associated olfactory stimuli reinstate ethanol-seeking behavior after extinction and modify extracellular dopamine levels in the nucleus accumbens.
BACKGROUND
Alcohol craving or automatic behavioral responses provoked by alcohol-related cues are thought to contribute to relapse risk in abstinent individuals. However, there is to date only limited direct experimental evidence that supports this hypothesis. The present study employed an operant response-reinstatement model to examine the effects of ethanol-associated environmental stimuli on alcohol-seeking behavior and extracellular dopamine (DA) levels in the nucleus accumbens (NAcc).


METHODS
Male Wistar rats were prepared with intracerebral guide cannulae for microdialysis and trained to operantly self-administer ethanol in the presence of discrete olfactory discriminative stimuli (Sdelta's) signaling the availability of ethanol (10% w/v) versus a nonrewarding stimulus (a 50 microM quinine HCl solution). After the discrimination learning phase, responding for ethanol (and quinine) was extinguished by withholding the drinking solutions as well as the corresponding Sdelta's. After reaching and maintaining an extinction criterion of < or = 5 responses/session, the rats were exposed noncontingently to the ethanol and nonreward Sdelta's but without the availability of ethanol or quinine.


RESULTS
The ethanol Sdelta's, but not nonreward Sdelta's, elicited significant recovery of responding. Exposure to the operant chamber during a 20 min "waiting period" before presentation of the Ss's was associated with a small but significant increase in dialysate DA levels. Subsequent exposure to the ethanol Sdelta and onset of the reinstatement session was accompanied by a small but significant decrease in DA efflux. Exposure to the nonreward Sdelta did not alter DA levels.


CONCLUSIONS
The behavioral data confirm that ethanol-predictive discriminative stimuli reliably elicit ethanol-seeking behavior after extinction. The increase in DA efflux during the waiting period confirms earlier findings and suggests that anticipation of access to ethanol activates mesolimbic DA neurons. The decrease in DA efflux after onset of the reinstatement session in animals that were presented with the ethanol Sdelta's may reflect neurochemical events associated with the mismatch between the predicted (i.e., ethanol availability) and actual (i.e., absence of ethanol) stimulus events. This possibility is supported by the lack of changes in DA efflux in rats that were presented with the nonreward Sdelta's, a test condition that did not involve such a mismatch. Overall, the findings provide further evidence for a role of conditioning processes in the control of alcohol-seeking behavior and, by extension, support the hypothesis that conditioned responses to drug-related stimuli may be an important factor in chronic alcohol abuse and relapse.
Katner
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The Scripps Research Institute, Department of Neuropharmacology, La Jolla, California 92037, USA. skatner@itsa.ucsf.edu
Weiss
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D000818:Animals; D016739:Behavior, Addictive / Q000378:metabolism* / Q000523:psychology; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D004193:Discrimination Learning / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism*; D000431:Ethanol / Q000008:administration & dosage*; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration / Q000523:psychology; D012903:Smell
D002492:Central Nervous System Depressants; D000431:Ethanol; D004298:Dopamine