Cocaine-predictive stimulus induces drug-seeking behavior and neural activation in limbic brain regions after multiple months of abstinence: Reversalby D-1 antagonists

The conditioning of cocaine's subjective actions with environmental stimuli may be a critical factor in long-lasting relapse risk associated with coca ine addiction. To study the significance of learning factors in persistent addictive behavior as well as the neurobiological basis of this phenomenon, rats were trained to associate discriminative stimuli (SD) with the availa bility of i.v. cocaine vs. nonrewarding saline solution, and then placed on extinction conditions during which the i.v. solutions and S(D)s were withh eld. The effects of reexposure to the SD on the recovery of responding at t he previously cocaine-paired lever and on Fos protein expression then were determined in two groups. One group was tested immediately after extinction , whereas rats in the second group were confined to their home cages for an additional 4 months before testing, In both groups, the cocaine SD, but no t the non-reward SD, elicited strong recovery of responding and increased F os immunoreactivity in the basolateral amygdala and medial prefrontal corte x (areas Cg1/Cg3). The response reinstatement and Fos expression induced by the cocaine SD were both reversed by selective dopamine D-1 receptor antag onists. The undiminished efficacy of the cocaine SD to elicit drug-seeking behavior after 4 months of abstinence parallels the long-lasting nature of conditioned cue reactivity and cue-induced cocaine craving in humans, and c onfirms a significant role of learning factors in the long-lasting addictiv e potential of cocaine. Moreover, the results implicate D-1-dependent neura l mechanisms within the medial prefrontal cortex and basolateral amygdala a s substrates for cocaine-seeking behavior elicited by cocaine-predictive en vironmental stimuli.