Article Figures & Data
Figures
- 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)].
Tables
- TABLE 1
Relative scope of the problem: opioids vs. alcohol
Data for opioid misuse, alcohol use, OUD, and AUD are from Substance Abuse and Mental Health Services Administration (2019). Data for opioid- and alcohol-related emergency department visits are from the Nationwide Emergency Department Sample (NEDS), Healthcare Cost and Utilization Project (HCUP), of the Agency for Healthcare Research and Quality, Rockville, MD (www.hcup-us.ahrq.gov/nedsoverview.jsp) and White et al. (2018). Data for for opioid overdose deaths and combined alcohol + opioid overdose deaths are from Hedegaard et al. (2020). Data for alcohol-related deaths are from Centers for Disease Control and Prevention (www.cdc.gov/ARDI).
Opioids Alcohol Misuse: 10,250,000a Use: 179,289,000 % of population: 3.7% % of population: 65.5% Opioid use disorder: 2,028,000 Alcohol use disorder: 14,818,000 % of population: 0.7% % of population: 5.4% Emergency department visits Emergency department visits Primary reason: 408,079 Primary reason: 1,714,757 All opioid-related: 1,461,770 All alcohol-related: 4,936,690 Deaths Deaths Total overdoses: 46,802 Total deaths: ∼95,000 Prescription opioids: 14,975 Acute overdose/injury: 44,080 Fentanyl and similar: 31,335 Chronic liver/cancer: 51,078 Heroin: 14,996 Opioid + alcohol-related deaths: 7143b - TABLE 2
Molecular and neurocircuitry targets for medications development to reverse hyperkatifeia of the withdrawal/negative affect stage for OUD and AUD
Target Manipulation Opioids Alcohol Within-system Dopamine Dopamine receptor partial agonists ✓ ✓ Opioid peptides G protein modulators ✓ — CREB ✓ — cAMP/PKA modulators — ✓ CREB — ✓ GABA/glutamate GABA subunit receptor agonists ✓ ✓ Glutamate receptor antagonists ✓ ✓ Between-system CRF CRF1 receptor antagonists ✓ ✓ Dynorphin κ-Opioid receptor antagonists ✓ ✓ Vasopressin V1b receptor antagonists ✓ ✓ Norepinephrine α1-Adrenergic receptor antagonists ✓ ✓ α2-Adrenergic receptor agonists ✓ ✓ β-Adrenergic receptor antagonists ✓ ✓ Hypocretin Hcrt-1 receptor antagonists ✓ ✓ Hcrt-2 receptor antagonists ✓ ✓ Neuroimmune system Neuroimmune modulators Tumor necrosis factor ✓ ✓ Phosphodiesterase inhibitors — ✓ Antistress modulators NPY Y1 receptor agonists ✓ ✓ Y2 receptor antagonists ✓ ✓ Nociceptin Nociceptin receptor agonists ✓ ✓ Endocannabinoids FAAH inhibitors ✓ ✓ MAGL inhibitors ✓ ✓ Oxytocin Oxytocin receptor agonists ✓ ✓ Hyperalgesia/pain Glutamate NMDA receptor antagonists ✓ ✓ CRF CRF1 receptor antagonists ✓ ✓ Dynorphin κ-Opioid receptor antagonists ✓ — Melanocortin Melanocortin receptor 4 antagonists ✓ ✓ PKC PKCε inhibitor — ✓ PKCγ inhibitor ✓ — Serotonin 5-HT2A receptor antagonist — ✓ PKA, protein kinase A; —, no data available; 5-HT2A, 5-hydroxytryptamine-2A.
In this issue
Jump to section
- Article
- Abstract
- I. Introduction
- II. Addiction: Definition and Theoretical Framework
- III. Within-System/Between-System Neurobiological Substrates for Hyperkatifeia Associated with Opioid and Alcohol Withdrawal
- IV. Within-System Neurobiological Substrates for Hyperkatifeia Associated with Opioid and Alcohol Withdrawal
- V. Between-System Neurobiological Substrates for Hyperkatifeia Associated with Opioid and Alcohol Withdrawal
- VI. Antistress Neurotransmitters/Neuromodulators and Hyperkatifeia
- VII. Hyperkatifeia and Sex Differences
- VIII. Pain, Hyperkatifeia, and Addiction
- IX. Individual Differences in Hyperkatifeia
- X. The Case for Hyperkatifeia as a Target for Medications Development
- Acknowledgments
- Authorship Contributions
- Footnotes
- Abbreviations
- References
- Figures & Data
- Info & Metrics
- eLetters