Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development

Abstract

Compulsive drug seeking that is associated with addiction is hypothesized to follow a heuristic framework that involves three stages (binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation) and three domains of dysfunction (incentive salience/pathologic habits, negative emotional states, and executive function, respectively) via changes in the basal ganglia, extended amygdala/habenula, and frontal cortex, respectively. This review focuses on neurochemical/neurocircuitry dysregulations that contribute to hyperkatifeia, defined as a greater intensity of negative emotional/motivational signs and symptoms during withdrawal from drugs of abuse in the withdrawal/negative affect stage of the addiction cycle. Hyperkatifeia provides an additional source of motivation for compulsive drug seeking via negative reinforcement. Negative reinforcement reflects an increase in the probability of a response to remove an aversive stimulus or drug seeking to remove hyperkatifeia that is augmented by genetic/epigenetic vulnerability, environmental trauma, and psychiatric comorbidity. Neurobiological targets for hyperkatifeia in addiction involve neurocircuitry of the extended amygdala and its connections via within-system neuroadaptations in dopamine, enkephalin/endorphin opioid peptide, and γ-aminobutyric acid/glutamate systems and between-system neuroadaptations in prostress corticotropin-releasing factor, norepinephrine, glucocorticoid, dynorphin, hypocretin, and neuroimmune systems and antistress neuropeptide Y, nociceptin, endocannabinoid, and oxytocin systems. Such neurochemical/neurocircuitry dysregulations are hypothesized to mediate a negative hedonic set point that gradually gains allostatic load and shifts from a homeostatic hedonic state to an allostatic hedonic state. Based on preclinical studies and translational studies to date, medications and behavioral therapies that reset brain stress, antistress, and emotional pain systems and return them to homeostasis would be promising new targets for medication development. SIGNIFICANCE STATEMENT: The focus of this review is on neurochemical/neurocircuitry dysregulations that contribute to hyperkatifeia, defined as a greater intensity of negative emotional/motivational signs and symptoms during withdrawal from drugs of abuse in the withdrawal/negative affect stage of the drug addiction cycle and a driving force for negative reinforcement in addiction. Medications and behavioral therapies that reverse hyperkatifeia by resetting brain stress, antistress, and emotional pain systems and returning them to homeostasis would be promising new targets for medication development.

Fig. 1.

Conceptual framework for the neurobiological basis of substance use disorders, involving a three-stage cycle—binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. These three stages involve dysregulations in three functional domains (incentive salience/pathological habits, negative emotional states, and executive function) that are mediated by three major neurocircuitry elements (basal ganglia, extended amygdala, and prefrontal cortex, respectively). ACC, anterior cingulate cortex; dlPFC, dorsolateral prefrontal cortex; DS, dorsal striatum; GP, globus pallidus; HPC, hippocampus; OFC, orbitofrontal cortex; PAG, periaqueductal gray; Thal, thalamus; vlPFC, ventrolateral prefrontal cortex; vmPFC, ventromedial prefrontal cortex. [Modified with permission from Koob and Volkow (2010)].

Fig. 2.

Conceptual framework of sources of reinforcement in addiction. Positive reinforcement, in which the drug typically engenders positive hedonic effects, is defined as an increase in the probability of responding that is produced by the presentation of a drug. Positive reinforcement is associated with the early stages of addiction as part of the binge/intoxication stage but persists throughout the addiction cycle. Negative reinforcement is defined as an increase in the probability of responding for a drug to relieve hyperkatifeia or stress, in which drug withdrawal during the withdrawal/negative affect stage of the addiction cycle typically engenders hyperkatifeia and stress. Both sources of reinforcement can coexist and be perpetuated by protracted abstinence and cue-, drug-, and stress-induced reinstatement in the preoccupation/anticipation stage of the addiction cycle. [Figure modified from an original diagram from Dr. Loren Parsons].

Fig. 3.

Validation of three neurofunctional domains in AUD by deep behavioral phenotyping. These three domains of incentive salience, negative emotionality, and executive function correspond to the binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation stages, respectively. Three neurobiological domains that are hypothesized to be critical for the addiction cycle were identified through factor analysis in a large and diverse clinical sample that represented the spectrum of AUD. Measures of addiction, personality, cognition, behavior, and exposure to early life stress were collected in 454 patients in 2015 and 2016 at the clinical Center at the National lnstitutes of Health (Kwako et al., 2019). The study confirmed the relevance of the three neurofunctional domains to AUD. Using a multiple-indicators, multiple-causes (MIMIC) approach, early life stress and sociodemographic predictors were identified. ADHD, attention-deficit/hyperactivitiy disorder; MADRS, Montgomery-Asberg Depression Rating Scale. [Figure based on results of Kwako et al. (2019)].

Fig. 4.

Within-system neurocircuitry associated with hyperkatifeia in the withdrawal/negative affect stage. Note the loss of dopamine and opioid peptide function in ventral tegmental area-nucleus accumbens circuitry, with a hypothesized contribution of the habenula that suppresses neuron activity in the ventral tegmental area and dynorphin that suppresses dopamine release in the nucleus accumbens. The extended amygdala is composed of several basal forebrain structures, including the bed nucleus of the stria terminalis, the central nucleus of the amygdala, and possibly a transition area in the medial portion (shell) of the nucleus accumbens. ACC, anterior cingulate cortex; DA, dopamine; dlPFC, dorsolateral prefrontal cortex; DS, dorsal striatum; GP, globus pallidus; HPC, hippocampus; LDT, laterodorsal tegmentum; OFC, orbitofrontal cortex; PAG, periaqueductal gray; PPT, pedunculopontine tegmentum; Thal, thalamus; vlPFC, ventrolateral prefrontal cortex; vmPFC, ventromedial prefrontal cortex; VTA, ventral tegmental area. [Adapted with permission from Koob (2008); George and Koob (2013)].

Fig. 5.

Between-system extended amygdala circuitry associated with hyperkatifeia in the withdrawal/negative affect stage. Note the gain of stress neurotransmitter and neuromodulator function and the loss of antistress neurotransmitter and neuromodulator function throughout the neurocircuitry of the extended amygdala. The extended amygdala is composed of several basal forebrain structures, including the bed nucleus of the stria terminalis, the central nucleus of the amygdala, and possibly a transition area in the medial portion (shell) of the nucleus accumbens. ACC, anterior cingulate cortex; dlPFC, dorsolateral prefrontal cortex; DS, dorsal striatum; GP, globus pallidus; HPC, hippocampus; OFC, orbitofrontal cortex; Thal, thalamus; vlPFC, ventrolateral prefrontal cortex; vmPFC, ventromedial prefrontal cortex; VTA, ventral tegmental area. [Taken with permission from George and Koob (2013)].

Fig. 6.

Allostatic change in emotional state associated with the transition to addiction, illustrating the progression of dependence over time and the shift in underlying motivational mechanisms. From initial, positive-reinforcing, pleasurable effects of the drug, the addictive process progresses to a point at which it is maintained by negative-reinforcing relief from a negative emotional state. The figure shows a schematic description of the opponent process from an allostatic perspective. The a-process (a) represents a positive hedonic or positive mood state, and the b-process (b) represents the negative hedonic or negative mood state. The affective stimulus (state) has been argued to be the sum of both the a-process and b-process. An individual who experiences a positive hedonic mood state from a drug of abuse with sufficient time between readministering the drug is hypothesized to retain the normal set point. An appropriate counteradaptive opponent process (b-process) that balances the activational process (a-process) does not lead to an allostatic state. Changes in the affective stimulus (state) in an individual with repeated frequent drug use may represent a transition to an allostatic state in brain reward systems and, by extrapolation, a transition to addiction. Notice that the apparent b-process never returns to the original homeostatic level before drug taking begins again, thus creating a progressively greater allostatic state in the brain reward system. The counteradaptive opponent process (b-process) does not balance the activational process (a-process) but in fact shows residual hysteresis. Although these changes that are illustrated in the figure are exaggerated and condensed over time, the hypothesis is that even during post-detoxification (a period of protracted abstinence), the reward system still bears allostatic changes. Notice the allostatic loads to the system as described in the text include genetics/epigenetics, childhood trauma, psychiatric comorbidity, and excessive drug taking. The following definitions apply: allostasis, the process of achieving stability through change; allostatic state, a state of chronic deviation of the regulatory system from its normal (homeostatic) operating level; allostatic load, the cost to the brain and body of the deviation that accumulate over time, reflecting in many cases pathological states and the accumulation of damage. [Modified with permission from Koob and Le Moal (2001)].