The development of substance abuse problems occurs due to a diverse combination of risk factors. Among these risks, studies have reported depression and early-life stress as of importance. These two factors often occur simultaneously, however, there is a lack of understanding of how their combined effect may impact vulnerability to drug abuse in adolescence. The present study used rats with different vulnerability to depression (Wistar and Wistar-Kyoto) to investigate the impact of maternal separation (MS) on emotional state and drug addiction vulnerability during the adolescence period. Mothers and their litters were subjected to MS (180 min/day) from postnatal day 2 to 14. The offspring emotional state was assessed by observing their exploratory behavior. Drug abuse vulnerability was assessed through conditioning to cocaine. MS impacted the emotional state in both strains. Wistar responded with increased exploration, while Wistar-Kyoto increased anxiety-like behaviours. Despite the different coping strategies displayed by the two strains when challenged with the behavioural tests, drug conditioning was equally impacted by MS in both strains. Early-life stress appears to affect drug abuse vulnerability in adolescence independently of a depression background, suggesting emotional state as the main driving risk factor. The development of substance abuse problems occurs due to an almost unpredictable combination of risk factors. Among the common risk factors, mental disorder and emotional stress are constantly cited as important 1,2. Among the main mental disorders, depression is one of the most common in adolescents, inspiring great concern due to its acute and long-lasting consequences 3. Depression in adolescence affects the physical, emotional and social development and can persist and recur into adulthood 4,5. Addiction and depression can be described as having a bidirectional relationship, in which individuals that use drugs for recreational purposes are more likely to develop depression, while individuals that suffer from depression are more likely to develop addiction due to the consumption of drugs (or alcohol) to cope with the depressive symptoms 6,7. Of note, depression and drug abuse comorbidity is highly prevalent in adolescence 8. Similarly to depression, emotional stress and its impact on one's physical and affective condition may lead to the development of addiction. Furthermore, it is known that early life stress, such as children carelessness and mistreatment, can also induce anxiety and depression in adulthood 9. This issue becomes especially relevant given the likelihood of the co-occurrence of these risk factors during early life. There is increased awareness about