Individual differences in the neuropsychopathology of addiction

Figures & data

Figure 1 (Left) Three stages of the addiction cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. These three stages reflect incentive salience/pathological habits, reward deficits/stress surfeit, and executive function deficits, respectively, to provide a powerful impetus for compulsive drug-seeking behavior associated with drug addiction. These domains of dysfunction correspond to neuroadaptations that reflect allostatic changes in three key neurocircuits to mediate compulsive drug seeking: basal ganglia, extended amygdala, and prefrontal cortex, respectively. (Top right) The progression of alcohol dependence over time. The schematic illustrates the shift in underlying motivational mechanisms. From initial, positively reinforcing, pleasurable alcohol effects, the addictive process progresses over time to being maintained by negatively reinforcing relief from a negative emotional state. (Bottom right) The a-process represents a positive hedonic or positive mood state, and the b-process represents a 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 a-process. 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 the 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. 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, accumulating over time, and reflecting in many cases pathological states and accumulation of damage. Bottom right panel from reference 3: Koob GF, Le Moal M. Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology. 2001 ;24(2):971 29. Copyright © Nature Publishing Group, 2001 . Top right panel from reference 4: Heilig M, Koob GF. A key role for corticotropin-releasing factor in alcohol dependence. Trends Neurosci. 2007;30(8):399-406. Copyright © Elsevier Applied Science Publishing, 2007

Figure 2 Schematic of the progression of drug addiction over time, illustrating the shift in underlying motivational mechanisms. From initial, positive reinforcing, pleasurable drug effects, the addictive process progresses over time to being maintained by negative-reinforcing relief from a negative emotional state. Adapted from reference 6: Koob GF. Theoretical frameworks and mechanistic aspects of alcohol addiction: alcohol addiction: alcohol addiction as a reward deficit disorder. In: Sommer WH, Spanagel R, eds. Behavioral Neurobiology of Alcohol Addiction. Berlin, Germany: Springer-Verlag; 2013:3-30. Current Topics in Behavioral Neuroscience; vol 13. © 2011, Springer-Verlag Berlin Heidelberg

Figure 3 (Opposite) Neural circuitry associated with the three stages of the addiction cycle. (A) Binge/intoxication stage. Reinforcing effects of drugs may engage associative mechanisms and reward neurotransmitters in the nucleus accumbens shell and core and then engage stimulusresponse habits that depend on the dorsal striatum. Two major neurotransmitters that mediate the rewarding effects of drugs of abuse are dopamine and opioid peptides. (B) Withdrawal/negative affect stage. The negative emotional state of withdrawal may engage the activation of the extended amygdala. The extended amygdala is composed of several basal forebrain structures, including the bed nucleus of the stria terminalis, central nucleus of the amygdala, and possibly a transition area in the medial portion (or shell) of the nucleus accumbens. Major neurotransmitters in the extended amygdala that are hypothesized to play a role in negative reinforcement are corticotropinreleasing factor, norepinephrine, and dynorphin. The extended amygdala has major projections to the hypothalamus and brain stem. (C) Preoccupation/anticipation (craving) stage. This stage involves the processing of conditioned reinforcement in the basolateral amygdala and processing of contextual information in the hippocampus. Executive control depends on the prefrontal cortex and includes the representation of contingencies, the representation of outcomes, their value, and subjective states (ie, craving and, presumably, feelings) associated with drugs. The subjective effects, termed drug craving in humans, involves activation of the orbitofrontal and anterior cingulate cortex and temporal lobe, including the amygdala, in functional imaging studies. A major neurotransmitter that is involved in the craving stage is glutamate that is localized in pathways from frontal regions and the basolateral amygdala that project to the ventral striatum. ACC, anterior cingulate cortex; BNST, bed nucleus of the stria terminalis; CeA, central nucleus of the amygdala; CRF, corticotropin-releasing factor; dlPFC, dorsolateral prefrontal cortex; DS, dorsal striatum; GABA, γ-aminobutyric acid; GP, globus pallidus; HPC, hippocampus; NAc, nucleus accumbens; OFC, orbitofrontal cortex; Thai, thalamus; vIPFC, ventrolateral prefrontal cortex; vmPFC, ventromedial prefrontal cortex. Modified with permission from reference 14: Koob GF, Everitt BJ, Robbins TW. Reward, motivation, and addiction. In: Squire LG, Berg D, Bloom FE, Du Lac S, Ghosh A, Spitzer N, eds. Fundamental Neuroscience. 3rd edition. Amsterdam, the Netherlands: Academic Press; 2008:987-1016. Copyright © Academic Press, 2008