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 (S Delta's) signaling the availability of ethanol (10% w/v) versus a nonrewarding stimulus (a 50 mu M 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 S Delta's. After reaching and maintaining an extinction criterion of less than or equal to 5 responses/session, the rats were exposed noncontingently to the ethanol and nonreward S Delta's but without the availability of ethanol or quinine. Results: The ethanol S Delta's, but not nonreward Sh's, elicited significant recovery of responding. Exposure to the operant chamber during a 20 min "waiting period" before presentation of the S Delta's was associated with a small but significant increase in dialysate DA levels. Subsequent exposure to the ethanol S Delta and onset of the reinstatement session was accompanied by a small but significant decrease in DA efflux. Exposure to the nonreward S Delta 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 Sh'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 S Delta'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.