Examines the hypothesis that negative affective states can contribute to the reinforcement associated with drug taking by changing the set point for hedonic processing or the set point for simply relieving physical or mental discomfort. The authors review research on the neuronal substrates for negative reinforcement and the conditioned reinforcing effects that contribute to both continued drug use and relapse after the" drug free" state has been achieved. Topics addressed include (1) dysregulation of neuronal elements of reward,(2) compromised positive reinforcement neurochemical mechanisms,(3) recruitment of stress/aversive systems,(4) molecular and cellular adaptations, and (6) continued vulnerability of reward and stress systems during protracted abstinence. The roles of stress and individual differences in the neurobiology of relapse and vulnerability relapse are explored.(PsycINFO Database Record (c) 2018 APA, all rights reserved)