The aim of this study was to determine the possible involvement of the neurosteroid dehydroepiandrosterone (DHEA) in cocaine-seeking behavior in a self-administration model in rats. DHEA pretreatment (continued thereafter concomitantly with cocaine self-administration) attenuated cocaine-seeking behavior and elevated the levels of dopamine and serotonin in several brain regions relevant to cocaine addiction. Chronic cocaine self-administration induced elevation in brain DHEA, its sulfate ester, DHEAS, and pregnenolone. The increased brain DHEA following cocaine self-administration may serve as a compensatory protective mechanism geared to attenuate the craving for cocaine. Such anti-craving activity is further enhanced by DHEA treatment before and during cocaine self-administration.