The chapter explores the role of brain stress systems and antistress systems in drug addiction, emphasizing the neuropharmacological function of extrahypothalamic systems in the extended amygdala. Drug addiction is characterized by compulsive drug use and loss of control, involving three stages: preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect. The activation of brain stress systems, such as the hypothalamic-pituitary-adrenal (HPA) axis, is hypothesized to play a key role in the negative emotional state that drives drug seeking through negative reinforcement mechanisms. The chapter discusses the dynamics of addiction, the interaction between stress and addiction, and the involvement of specific brain stress systems (corticotropin-releasing factor, norepinephrine, orexin, vasopressin, dynorphin) and antistress systems (neuropeptide Y, nociceptin/orphanin FQ) in the transition and maintenance of drug dependence. It highlights the potential of these systems as novel targets for treatment and prevention of addiction, providing insights into the organization and function of basic brain emotional circuitry.The chapter explores the role of brain stress systems and antistress systems in drug addiction, emphasizing the neuropharmacological function of extrahypothalamic systems in the extended amygdala. Drug addiction is characterized by compulsive drug use and loss of control, involving three stages: preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect. The activation of brain stress systems, such as the hypothalamic-pituitary-adrenal (HPA) axis, is hypothesized to play a key role in the negative emotional state that drives drug seeking through negative reinforcement mechanisms. The chapter discusses the dynamics of addiction, the interaction between stress and addiction, and the involvement of specific brain stress systems (corticotropin-releasing factor, norepinephrine, orexin, vasopressin, dynorphin) and antistress systems (neuropeptide Y, nociceptin/orphanin FQ) in the transition and maintenance of drug dependence. It highlights the potential of these systems as novel targets for treatment and prevention of addiction, providing insights into the organization and function of basic brain emotional circuitry.