Theoretical frameworks and mechanistic aspects of alcohol addiction: alcohol addiction as a reward deficit disorder.

(Top left) Diagram showing the stages of impulse control disorder and compulsive disorder cycles related to the sources of reinforcement. In impulse control disorders, an increasing tension and arousal occurs before the impulsive act, with pleasure, gratification, or relief during the act. Following the act, there may or may not be regret or guilt. In compulsive disorders, there are recurrent and persistent thoughts (obsessions) that cause marked anxiety and stress followed by repetitive behaviors (compulsions) that are aimed at preventing or reducing distress (American Psychiatric Association 1994). Positive reinforcement (pleasure/gratification) is more closely associated with impulse control disorders. Negative reinforcement (relief of anxiety or relief of stress) is more closely associated with compulsive disorders. (Top right) Collapsing the cycles of impulsivity and compulsivity results in the addiction cycle, conceptualized as three major components: preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect (Taken with permission from Koob 2008b.)(Bottom) Change in the relative contribution of positive and negative reinforcement constructs during the development of substance dependence on alcohol

a Withdrawal from a single boul of acute ethanol intoxication (week 1) resulted in a significant but transient increase in brain reward threshold only with the highest dose of ethanol tested (2.0 g/kg: aP < 0.05, compared with vehicle controls at given time-point post-injection). The effect was significant at 6 hours, a time when blood alcohol levels had declined to virtually undetectable levels following this dose of ethanol. Repeated treatment with this dose for two additional weeks resulted in a progressive broadening of the duration of significant threshold elevations. By comparison, treatment with 1.5 g/kg ethanol resulted in significant but transient elevations only after three repeated bouts of intoxication/withdrawal, and no statistically reliable changes were seen after one or two treatments (data not shown). Treatment with 1.0 g/kg did not produce any statistically reliable threshold changes regardless of treatment week (data not shown). Data are expressed as mean ± SEM percentage of baseline threshold, n = 8–10 per dose group. [Taken with permission from Schulteis and Liu 2006.] b Time-dependent elevation of intracranial self-stimulation thresholds during ethanol withdrawal. Mean blood alcohol levels were 197.29 mg%, Data are expressed as mean ± SEM percentage of baseline threshold, ap < 0.05, thresholds that were significantly elevated above control levels at 2–48 hours post-ethanol. Open circles indicate the control condition. Closed circles indicate the ethanol withdrawal condition. [Taken with permission from Schulteis et al. 1995.]

Pathways for key elements of addiction circuitry implicated in negative emotional states. Addiction circuitry is composed of structures involved in the three stages of the addiction cycle: binge/intoxication (ventral striatum, dorsal striatum and thalamus), withdrawal/negative affect (ventral striatum, bed nucleus of the stria terminalis and central nucleus of the amygdala), preoccupation/anticipation (prefrontal cortex, orbitofrontal cortex and hippocampus). Highlighted here for the withdrawal/negative affect stage is increased activity in the extended amygdala and decreased activity in the reward system, illustrated with the use of imaging colors (i.e., red for high activity and blue for low activity). Modified with permission from Blackburn-Munro and Blackburn-Munro (2003) and Koob et al. (2008). AMG, amygdala; BNST, bed nucleus of the stria terminalis; DS, dorsal striatum; GP, globus pallidus; Hippo, hippocampus; Hyp, hypothalamus; Insula, insular cortex; OFC, orbitofrontal cortex; PFC, prefrontal cortex; Thal, thalamus; VS, ventral striatum; and VTA, ventral tegmental area. [Modified with permission from Zald and Kim 2001]

a Schematic of the progression of alcohol dependence over time, illustrating the shift in underlying motivational mechanisms. From initial, positive reinforcing, pleasurable alcohol effects, the addictive process progresses over time to being maintained by negative reinforcing relief from a negative emotional state. Data presented in this paper suggest that neuroadaptations encompassing the recruitment of extrahypothalamic CRF systems are key to this shift. (Taken with permission from Heilig and Koob 2007.) b The a-process represents a positive hedonic or positive mood state, and the b-process 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 re-administering 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. The 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 systems and, by extrapolation, a transition to addiction (see text). Notice that the apparent b-process never returns to the original homeostatic level before drug taking begins again, thus creating a greater and greater allostatic state in the brain emotional systems. The counteradaptive opponent-process (b-process) does not balance the activational process (a-process) but in fact shows a residual hysteresis. Although these changes illustrated in the figure are exaggerated and condensed over time, the hypothesis is that even during post-detoxification (a period of “protracted abstinence”), the brain emotional systems still bear allostatic changes (see text). The following definitions apply: alkalosis, 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. [Modified with permission from Koob and Le Moal 2001.]