Addiction is a complex disease process of the brain that results from recurring drug intoxication and is modulated by genetic, developmental, experiential, and environmental factors. The neurobiological changes that accompany drug addiction are not well understood. While until recently it was believed that addiction predominantly involved reward processes mediated by limbic circuits (see, for example, the reward deficiency syndrome [1
]), results from recent neuroimaging studies have implicated additional brain areas, especially the frontal cortex. Here we summarize the findings from these neuroimaging studies and incorporate them with pertinent results from preclinical studies in suggesting a basis for an integrated model of drug addiction.
Most imaging studies have concentrated on the involvement of dopamine in the process of drug addiction because the ability of drugs of abuse to increase brain dopamine concentration in limbic brain regions is considered crucial for their reinforcing effects (2
). However, the increase in dopamine per se is insufficient to account for the process of addiction, since drugs of abuse increase dopamine in naive as well as in addicted subjects. In fact, in the case of cocaine addiction, the magnitude of drug-induced dopamine increases, and the intensity of self-reports of the drug’s reinforcing properties (the “high”), appears to be smaller in addicted than in naive subjects (4
). This implies that dopamine involvement in drug addiction is likely to be mediated by means of functional and structural changes in the circuits that are modulated by dopamine, including the frontal cortex. In support of this suggestion are the findings of several recent structural/volumetric magnetic resonance imaging studies documenting morphological changes in the frontal lobe in various forms of drug addiction. For example, frontal lobe volume losses have been identified in cocaine-dependent subjects (5
), alcoholic subjects (7
), and heroin-dependent subjects (5
). The latter study noted negative correlations between normalized prefrontal volumes and years of either cocaine or heroin use, implying a cumulative effect of substance abuse on frontal volumes. Additional support is provided by studies done in rats. For example, it has been recently shown that self-administration of cocaine, but not food, results in morphological changes in dendrites and dendritic spines in the prefrontal cortex and nucleus accumbens (10
). Dopamine activation, as seen during amphetamine administration, also suppresses the inhibition of the amygdala by the medial prefrontal cortex, possibly leading to a disinhibition of sensory-driven affective responses (11
). A similar process may be occurring in human drug addiction, in which prefrontal top-down processes (see reference 12
) are reduced, releasing behaviors that are normally kept under close monitoring and simulating stress-like reactions in which inhibitory control is suspended and stimulus-driven behavior is accentuated.
If the frontal cortex and its supervisory functions are indeed down-regulated in human drug addiction, the relevance of motivational, higher cognitive, and self-monitoring processes to this affliction cannot be overstated. Specifically, we propose that the behaviors and associated motivational states that are at the core of drug addiction are distinctly the processes of loss of self-directed/willed behaviors to automatic sensory-driven formulas and attribution of primary salience to the drug of abuse at the expense of other available rewarding stimuli. We hypothesize that these states are first evoked in the presence of the drug of abuse or cues conditioned to the drug but then become chronic action tendencies, contributing to relapse/bingeing (behavioral compulsion) and withdrawal/craving (mental compulsion, i.e., obsessiveness), respectively. We thus conceptualize drug addiction as a syndrome of impaired response inhibition and salience attribution and name it the “I-RISA” syndrome of drug addiction.
The I-RISA syndrome encompasses four clusters of behaviors that are interconnected in a positive feedback loop () and depend on the functioning of the prefrontal circuits vis-à-vis the subcortical reward pathway.
Behavioral Manifestations of the I-RISA (Impaired Response Inhibition and Salience Attribution) Syndrome of Drug Addiction