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Adolescence is a transitional period during development that is associated with a greater likelihood of addiction to drugs than any other age. One possibility for this observation is that learned associations between the rewarding experience of drugs and drug-related cues may produce greater motivational salience, and thus are more difficult to extinguish. Using an unbiased place-conditioning paradigm with two doses of cocaine (10 mg/kg or 20 mg/kg), the authors show here that adolescents require 75 +/- 17% more extinction trials than adults to extinguish cocaine place-preferences. Furthermore, once extinguished, adolescents display a greater preference for a previously cocaine-paired environment upon drug-primed reinstatement compared with adults. These results suggest that adolescent vulnerability to addiction involves robust memories for drug-associated cues that are difficult to extinguish. Therefore, drug-addicted adolescents may have a higher risk of relapse than adults, leading to greater prevalence of addiction in this population.

The present study examined the differential cocaine-induced activation of the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) throughout discrete zones of analysis of the nucleus accumbens (NAc) in rats. CREB-dependent gene transcription, which may underlie long-lasting drug-induced changes in behavior and the subjective effects of cocaine, varies depending on the stage of drug exposure or withdrawal and the cell population involved. Using immunohistochemistry, the authors analyzed changes in CREB phosphorylation in the NAc after 5 days of cocaine, a short or long drug-free period, and a subsequent challenge injection. The NAc shell was separated into 5 zones of analysis previously defined by neurochemistry and connectivity. Repeated cocaine resulted in CREB phosphorylation in all analyzed subregions of the NAc excluding the most ventrolateral region of the shell 2 weeks after cessation of repeated cocaine, but rats challenged after 2 drug-free days yielded a more localized activation of CREB in the 3 most dorsomedial zones of the shell. The temporal and anatomical determinants of cocaine-induced CREB activity may indicate functional differences among NAc shell subregions and suggest the involvement of CREB in early and late cocaine effects.