A model of how interactions between prefrontal cortex (PFC) subregions may regulate cognitive, emotional and behavioural changes in addiction. The model shows how changes in the activity of PFC subregions in addicted individuals relate to core clinical symptoms of addiction — intoxication and bingeing, and withdrawal and craving — compared to PFC activity in healthy, non-addicted individuals or states. The model focuses particularly on inhibitory control and emotion regulation. The blue ovals represent dorsal PFC subregions (including the dorsolateral PFC (DLPFC), the dorsal anterior cingulate cortex (dACC) and the inferior frontal gyrus; see ) that are involved in higher-order control (‘cold’ processes). The red ovals represent ventral PFC subregions (the medial orbitofrontal cortex (mOFC), the ventromedial PFC and rostroventral ACC) that are involved in more automatic, emotion-related processes (‘hot’ processes). Drug-related neuropsychological functions (for example, incentive salience, drug wanting, attention bias and drug seeking) that are regulated by these subregions are represented by darker shades and non-drug related functions (for example, sustained effort) are represented by lighter shades. a | In the healthy state, non-drug related cognitive functions, emotions and behaviours predominate (shown by the large light-coloured ovals) and automatic responses (emotions and action tendencies that could lead to drug taking) are suppressed by input from the dorsal PFC (shown by the thick arrow). Thus, if a person in the healthy state is exposed to drugs, excessive or inappropriate drug-taking behaviour is prevented or stopped (‘Stop!’). b | During craving and withdrawal, drug-related cognitive functions, emotions and behaviours start to eclipse non-drug related functions, creating a conflict regarding drug taking (‘Stop?’). Decreased attention and/or value is assigned to non-drug related stimuli (shown by smaller light-shaded ovals), and this reduction is associated with reduced self-control and with anhedonia, stress reactivity and anxiety. There is also an increase (shown by the larger dark-shaded ovals) in drug-biased cognition and cue-induced craving and drug wanting. c | During intoxication and bingeing, higher-order non-drug related cognitive functions (shown by the small light blue oval) are suppressed by increased input (shown by the thick arrow) from the regions that regulate drug-related, ‘hot’ functions (large dark red oval). That is, there is decreased input from higher-order cognitive control areas (shown by the thin dashed arrow), and the ‘hot’ regions come to dominate the higher-order cognitive input. Thus, attention narrows to focus on drug-related cues over all other reinforcers, impulsivity increases and basic emotions — such as fear, anger or love — are unleashed, depending on the context and individual predispositions. The result is that automatic, stimulus-driven behaviours, such as compulsive drug consumption, aggression and promiscuity, predominate (‘Go!’). This model does not take into account the challenge of localizing PFC functions or the evidence that some addicted individuals use drugs to ‘self-medicate’ in an attempt to normalize PFC functions (although part a could represent an approximation of the normalized PFC functions in these individuals).