Upon repeated use of a substance, the user develops neuroadaptive tolerance to the rewarding effects and an escalation of the dose is necessary to achieve the same initial pleasurable effects (Koob and Le Moal, 2001). As an individual continues further into the addiction cycle, neurochemical systems other than those involved in the positive rewarding effects of alcohol and drugs of abuse are recruited by chronic activation of the reward systems (Koob, 2013a, Koob, 2013b, Koob, 2013c, Koob and Le Moal, 2005). During this period, positive reinforcement associated with acute drug administration is gradually replaced by negative reinforcement, in which the drug is taken to prevent the emergence of negative emotional state (e.g. anxiety, irritability, dysphoria) when access to the drug is prevented. The switch to behavior driven by negative reinforcement is primarily mediated by brain stress systems (corticotrophin-release factor; CRF) in the HPA-axis and extended amygdala (Koob, 2008). Both stress- and drug-induced activation of the HPA-axis allows glucocorticoids to sensitize reward pathways, characterized by increases in reward thresholds during withdrawal (Koob and Kreek, 2007). As dependence and withdrawal develop, brain
