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181. Drug Addiction: The Gain in the Brain is in the Pain

      Addiction is a chronically relapsing disorder characterized by compulsive drug seeking that is hypothesized to derive from multiple sources of motivational dysregulation. The construct of negative reinforcement, defined as drug taking that alleviates a negative emotional state (hypohedonia, dysphoria, anxiety, hyperalgesia, irritability, and sleep disturbances) that is created by drug abstinence. The negative emotional state associated with addiction has been termed hyperkatifeia from the Greek “katifeia” for “dejection or sadness,” and is particularly relevant as a motivational driving force in both the withdrawal/negative affect and preoccupation/anticipation stages of the addiction cycle. The shift in motivation to negative reinforcement is termed the “dark side of addiction,” and is hypothesized to reflect an allostatic misregulation of hedonic tone such that drug taking makes the hedonic negative emotional state worse during the process of seeking temporary relief via compulsive drug taking. In animal models, repeated misuse of drugs of abuse results in negative emotion-like states reflected in increased reward thresholds, decreased pain thresholds, anxiety-like and dysphoric-like responses. Such negative emotional states that drive negative reinforcement are hypothesized to derive not only from “within system” dysregulation of key neurochemical circuits that mediate incentive-salience/reward systems (dopamine, opioid peptides) in the ventral striatum but also from the” between system” recruitment of brain stress systems (corticotropin-releasing factor, dynorphin, norepinephrine, hypocretin, vasopressin, glucocorticoids and neuroimmune factors) in the extended amygdala. Excessive drug taking is also accompanied by deficits in executive function produced by neurocircuitry dysfunction in the medial prefrontal cortex that may facilitate the transition to compulsive-like responding and relapse. Thus, compelling evidence exists to argue that plasticity in the brain pain emotional systems is triggered by acute excessive drug intake, is sensitized during the development of compulsive drug taking with repeated withdrawal, persists into protracted abstinence, and contributes to the development and persistence of compulsive drug seeking.
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