Pathophysiology of Addiction

Drug addiction, also referred to diagnostically as substance dependence, is a chronically relapsing brain disorder characterized by compulsive drug taking. Different drugs produce different patterns of addiction with three stages: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. In 2005, 22 million Americans, 9% of the population aged 12 and older, experienced abuse or dependence on alcohol or an illicit drug within the prior 12 months. An additional 25.1 million experienced nicotine dependence. The stages of progression of drug use show that the use of cigarettes (nicotine) or alcohol precedes the use of marijuana (cannabis) and, in turn, the use of marijuana precedes the use of other illicit drugs. Substance abuse and addiction contribute to various medical disorders, including pulmonary and cardiovascular disease, stroke, cancer, infectious diseases (HIV and hepatitis C), and mental disorders (i.e., anxiety disorder, psychoses). It is estimated that 40–60% of the vulnerability to addiction is attributable to genetic factors. The reinforcing effects of drugs during intoxication set the initial stage that, if perpetuated, triggers the neuronal adaptations that result in addiction. At least four systems have been identified as having an important role in the acute reinforcing effects of drugs abuse: the mesolimbic dopamine system, the opioid peptide system, the γ-aminobutyric acid system, and the endocannabinoid system localized to key circuits in the basal forebrain, including the nucleus accumbens and amygdala. Repeated perturbation of reward circuits (e.g., marked dopamine increases followed by dopamine decreases) results in consequent disruption of the circuits that it regulates (motivation/drive, memory/learning, and control). Addiction also involves a long-term, persistent plasticity in the activity of neural circuits mediating motivational systems that derives from recruitment of brain stress systems such as corticotropin-releasing factor that drive negative emotional states. Abnormalities in the prefrontal cortex including the anterior cingulate gyrus in drug-addicted subjects lead to inadequate decisions that favor immediate rewards over delayed but more favorable responses. The changes in plasticity of these circuits have been hypothesized to involve molecular neuroadaptations such as changes in intracellular signal transduction and/or changes in transcription of particular target genes that can lead to long-term altered neuronal activity and vulnerability to reentering the addictive cycle.