The emotional dysregulation that is associated with the withdrawal/negative affect stage also involves a between-system neuroadaptation, in which neuro-chemical systems other than those involved in the positive rewarding effects of drugs of abuse are recruited or dysregulated by chronic activation of the reward system.68 Both the hypothalamic-pituitary-adrenal axis and brain stress system mediated by CRF are dysregulated by the chronic administration of all major drugs with dependence or abuse potential, with a common response of elevated adrenocorticotropic hormone, corticosterone, and amygdala CRF during acute withdrawal.20,75 As tolerance and withdrawal develop, brain stress systems, such as CRF, norepinephrine, and dynorphin, are recruited in the extended amygdala and contribute to the development of negative emotional states in withdrawal and protracted abstinence (tables 1, 2, circuits 6–8).20,22 As a result, the concept of anti-reward was developed,2 based on the proposal that opponent processes that are a general feature of biological systems also act to limit reward.4 Multiple circuits are likely to contribute to the hypothesised opponent-like processes. During acute withdrawal from all drugs of abuse, CRF increases in the extended amygdala (tables 1,
