Perseveration of craving: effects of stimuli conditioned to drugs of abuse versus conventional reinforcers differing in demand

Associative learning is essential for establishing appropriate responses to cause-effect relationships and effective behavioral adjustments to environmental changes. However, learned associations also promote maladaptive behavior such as uncontrollable drug seeking in addicts exposed to drug-associated stimuli. Here, we sought to identify behavioral characteristics that distinguish reward seeking produced by environmental stimuli conditioned to highly potent but non-addictive conventional reinforcers from reward seeking induced by stimuli conditioned to addictive drugs. Rats were trained to associate discriminative (i.e. contextual) stimuli (S+) with availability of cocaine, ethanol, palatable sweet solutions or water during dehydration. Following extinction, response-reinstating effects of re-exposure to these stimuli were established in terms of magnitude and perseveration. Initially, the S+ produced strong reinstatement irrespective of association with conventional or drug reward. However, with repeated testing, S+-induced reward seeking decreased to extinction levels when motivated by the sweet solutions but perseverated when motivated by cocaine or ethanol. In rats placed on water restriction to induce a motivational constraint, the S+ supported perseverating reinstatement identical to that produced by an S+ conditioned to cocaine. The findings suggest that behavior guided by associations between environmental stimuli and drugs of abuse is characterized by perseverating, apparently highly extinction-resistant reward seeking, whereas behavior controlled by stimuli associated with conventional reward extinguishes rapidly in the absence of primary reinforcement. Reward seeking elicited by stimuli associated with natural reward can, however, become perseverative during physiological deprivation states. Possibly, perseverating drug seeking engages mechanisms overlapping with those that have evolved to promote alleviation of physiological deprivation to secure survival.