Long-lasting resistance to extinction of response reinstatement induced by ethanol-related stimuli: role of genetic ethanol preference

Background: The conditioning of ethanol's reinforcing effects with specific environmental stimuli is thought to be a critical factor in long-lasting relapse risk associated with alcoholism. To study the significance of such learning factors in the addictive potential of ethanol, this experiment was designed (1) to characterize the effects of stimuli associated with alcohol availability on the reinstatement of responding at a previously ethanol-paired lever in rats with genetically determined ethanol preference versus nonpreference and (2) to examine the persistence of the motivating effects of these stimuli over time. Methods: Male alcohol-preferring (P) and alcohol-nonpreferring (NP) rats were trained to operantly self-administer ethanol (10% w/v) or water on a fixed-ratio 1 schedule in a 30-min daily session. Ethanol and water sessions were scheduled in random sequence across training days. Ethanol availability was signaled by an olfactory discriminative stimulus (banana extract, S+), and each lever press was paired with brief presentation of the conditioning chamber's house light (CS+). The discriminative stimulus signaling water availability (i.e., nonreward) consisted of anise odor (S-), and lever-responses during water sessions were paired with a brief white noise generation (CS-). The rats then were placed on extinction conditions during which ethanol and water, as well as the corresponding stimuli, were withheld. The effects of noncontingent exposure to the S+ versus S- paired with response-contingent presentation of the CS+ versus CS- on responding at the previously active lever were then determined in 30-min reinstatement sessions. To study the resistance to extinction of the effects of the ethanol-associated stimuli, additional tests were conducted at 3-day intervals for a total of 50 days. Results: The number of ethanol-reinforced responses during self-administration training was significantly greater in P than in NP rats (p < 0.01). After extinction, a significant recovery of responding was observed in both groups of rats under the stimulus conditions associated with ethanol (S+/CS+) but not those associated with water (S-/CS-). However, the response reinstatement was significantly greater in P than NP rats (p < 0.01). In addition, the results revealed a considerable resistance to extinction to the effects of the ethanol-associated stimuli. Throughout the 50-day test period, responding remained significantly above extinction levels in both P and NP rats (p < 0.01), but with an overall greater number of responses in P than NP rats (p < 0.05). Conclusions: The results support the hypothesis that conditioning factors contribute importantly to compulsive ethanol seeking and long-lasting vulnerability to relapse. In addition, the results suggest that genetic predisposition toward heightened ethanol intake extends to greater susceptibility to the motivating effects of ethanol-related environmental stimuli.