In this narrative review, the neurobiological mechanisms underlying substance abuse and addiction are discussed with a particular emphasis on the mechanisms that promote ongoing use and relapse. Addiction is estimated to affect 10-15% or more of the adult population, including physicians. Genetic predisposition, psychological and environmental risk factors, the timing of exposure to the substance, the type of substance used, and the frequency of use influence the individual's susceptibility to addiction. Abused substances act on the brain's reward system, a neural circuit that produces pleasurable feelings in response to stimuli that promote survival, thereby modifying future behavior to seek out similar stimuli. Endogenous activators include food, sex, and social interaction. Drugs of abuse hijack the reward circuit, producing intense activation. Repetitive exposure to substances leads to persistent, altered genetic expression and accumulation of ΔFos-B and corticotropin-releasing factor. High levels of these substances suppress the reward circuit and activate the endogenous stress response, resulting in a generalized state of discord. These changes are enduring and can trigger substance use relapse even after long periods of abstinence.

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