The seeds of addiction are typically sown years prior to the onset of addictive substance use or engagement in addictive behaviors, due to the priming of the reward pathway (RewP) by alterations in the mechanism of stress-signaling from the hypothalamic-pituitary-adrenal axis (HPA) and related pathways. Excessive stress from a single-event and/or cumulative life experiences during childhood, such as those documented in the Adverse Childhood Experiences Study, is translated into neurobiological toxicity that alters the set-point of the HPA axis and limbic system homeostasis [suggested new term: regulation pathway (RegP)]. The resultant alteration of the RegP not only increases the risk for psychiatric and physical illness, but also that for early onset and chronic addictions by dysregulating the RewP. This paper reviews the interface of these symbiotic pathways that result in the phenotypic pathology of emotional dysregulation, cognitive impairment, and compulsive behaviors, as well as morbidity and shorter life expectancy when dysregulated by chronic stress.
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