Enduring resistance to extinction of cocaine-seeking behavior induced by drug-related cues

The conditioning of cocaine's pharmacological actions with environmental st imuli is thought to be a critical factor in long-lasting relapse risk assoc iated with cocaine addiction. To study the significance of environmental st imuli in enduring vulnerability to relapse, the resistance to extinction of drug-seeking behavior elicited by a cocaine-related stimulus was examined. Male Wistar rats were trained to associate discriminative stimuli (S-D) wi th the availability of intravenous cocaine (S+) vs. the availability of non -rewarding (S-) saline solution, and then placed on extinction conditions d uring which intravenous solutions and S-D were withheld. The rats were then presented with the S+ or S- alone in 60-min reinstatement sessions conduct ed at 3-day intervals. To examine the long-term persistence of the motivati ng effects of the cocaine S+, a subgroup of rats was re-tested following an additional three months of abstinence during which time the rats remained confined to their home cages. Re-exposure to the cocaine S+ selectively eli cited robust responding at the previously active lever. The efficacy and se lectivity of this stimulus to elicit responding remained unaltered througho ut a 34-day phase of repeated testing as well as following the additional e xtended abstinence period. In pharmacological tests, conducted in a separat e group of rats, the dopamine (DA) D-1 antagonist SCH 39166 (10 mug/kg), th e D-2/3 antagonist nafadotride (1 mg/kg), and the D-2/3 agonist PD 128907 ( 0.3 mg/kg) suppressed the cue-induced response reinstatement while the D-1 agonist SKF 81297 (1.0 mg/kg) produced a variable behavioral profile attenu ating cue-induced responding in some rats while exacerbating this behavior in others. The results suggest that the motivating effects of cocaine-relat ed stimuli are highly resistant to extinction. The undiminished efficacy of the cocaine S+ to induce drug-seeking behavior both with repeated testing and following long-term abstinence parallels the long-lasting nature of con ditioned cue reactivity and cite-induced cocaine craving in humans, and con firms a significant role of learning factors in long-lasting vulnerability to relapse associated with cocaine addiction. Finally, the results support a role of DA neurotransmission in cue-induced cocaine-seeking behavior. (C) 2001 American College of Neuropsychopharmacology. Published by Elsevier Sc ience Inc. All rights reserved.