Addiction and Loss of Control: Hyperkatifeia, Negative Reinforcement and the Dark Side of Addiction

Drug addiction is a chronically relapsing disorder characterized by loss of control and compulsive drug seeking within a heuristic framework comprised of a three stage addiction cycle. Such loss of control is hypothesized to derive from multiple sources of motivational dysregulation that occur in three functional domains that reflect the three stages of the addiction cycle: incentive salience/pathological habits in the binge/intoxication stage, negative emotional states in the withdrawal/negative affect stage, and executive function deficits in the preoccupation/anticipation stage. These three domains and stages are hypothesized to be mediated by three major neurocircuitry elements: basal ganglia, extended amygdala, and prefrontal cortex, respectively. A largely neglected source of loss of control in addiction is the via the construct of negative reinforcement driven by the emotional pain of drug withdrawal and protracted abstinence. The construct of negative reinforcement, defined as drug taking that alleviates a negative emotional state or hyperkatifeia (pain, hypohedonia, dysphoria, anxiety, hyperalgesia, irritability, and sleep disturbances) associated with drug abstinence following excessive drug taking. Such hyperkatifeia that drives negative reinforcement is hypothesized to derive from loss of function of key neurochemical circuits within the brain reward system in the basal ganglia and gain of function within the brain stress systems (corticotropin-releasing factor, dynorphin, norepinephrine, hypocretin, vasopressin, glucocorticoids and neuroimmune factors) in the extended amygdala. Compelling evidence exists to argue that hyperkatifeia triggered by acute excessive drug intake, is sensitized during the development of compulsive alcohol taking with repeated withdrawal, persists into protracted abstinence, and contributes to the development and persistence of compulsive, loss of control drug seeking. Significant overlap in the engagement in addiction of circuits mediating brain emotional pain and brain physical pain may help explain the prominent role of drugs in “deaths of despair” and the effects of social isolation on drug seeking in the covid-19 pandemic.