Loss of control over drug taking is considered a hallmark of addiction and is critical in relapse. Dysfunction of frontal brain regions involved with inhibitory control may underlie this behavior. We evaluated whether addicted subjects when instructed to purposefully control their craving responses to drug-conditioned stimuli can inhibit limbic brain regions implicated in drug craving. We used PET and 2-deoxy-2[18F]fluoro-D-glucose to measure brain glucose metabolism (marker of brain function) in 24 cocaine abusers who watched a cocaine-cue video and compared brain activation with and without instructions to cognitively inhibit craving. A third scan was obtained at baseline (without video). Statistical parametric mapping was used for analysis and corroborated with regions of interest. The cocaine-cue video increased craving during the no-inhibition condition (pre 3±3 post 6±3; p<0.001) but not when subjects were instructed to inhibit craving (pre 3±2 post 3±3). Comparisons with baseline showed visual activation for both cocaine-cue conditions and limbic inhibition (accumbens, orbitofrontal, insula, cingulate) when subjects purposefully inhibited craving (p<0.001). Comparison between cocaine-cue conditions showed lower metabolism with cognitive inhibition in right orbitofrontal cortex and right accumbens (p<0.005), which was associated with right inferior frontal activation (r = −0.62, P <0.005). Decreases in metabolism in brain regions that process the predictive (nucleus accumbens) and motivational value (orbitofrontal cortex) of drug-conditioned stimuli was elicited by instruction to inhibit cue-induced craving. This suggests that cocaine abusers may retain some ability to inhibit craving and that strengthening fronto-accumbal regulation may be therapeutically beneficial in addiction.
In addicted individuals exposure to conditioned drug-cues (i.e., places, people and paraphernalia associated with the drug) usually elicits an intense desire for the drug. This subjective experience (described as craving) frequently triggers relapse (O’Brien et al., 1998). Dopamine (DA) is a neurotransmitter involved with reward and with prediction of reward (Wise and Rompre, 1989; Schultz et al., 1997), and DA increases in the nucleus accumbens (NAcc) are associated with the drug-seeking behavior that follows exposure to conditioned-cues (Phillips et al., 2003; Weiss et al., 2000). These DA responses are modulated by glutamatergic projections from the frontal cortex (You et al., 2007; Yun et al., 2004; Taber et al., 1995), including the orbitofrontal cortex (OFC), which signals the motivational value of the conditioned stimuli (Rolls, 1996) and from amygdala and ventral hippocampus (Grace et al., 2007). It has been proposed that disrupted function of frontal regions may contribute to the impaired control over drug taking that characterizes drug addiction (Kalivas, 2004).
However, addicted individuals may retain some level of purposeful control over craving, but to our knowledge this has not been specifically evaluated. Here we performed a proof-of-principle study to test the hypothesis that a simple cognitive control procedure could reduce the subjective report of cue-induced craving in cocaine abusers, and to test the linked hypothesis that this would be associated with objective measures of inhibition of activity in brain regions (NAcc and OFC) that are implicated in the responses to drug conditioned stimuli.
To test these hypotheses we used Positron Emission Tomography (PET) and 2-deoxy-2[18F]fluoro-D-glucose (18FDG) to measure brain glucose metabolism (marker of brain function) ( Sokoloff et al., 1977) in 24 active cocaine abusers. Subjects were tested using a video of cocaine cues that was previously shown to induce the subjective report of craving and to increase objective measures of striatal DA in cocaine abusers (Volkow et al., 2006). The cocaine abusers were scanned during stimulation with the cocaine-cue video twice, both with instruction to try to purposefully inhibit craving (cognitive inhibition CI) and without instruction (no-inhibition NI). A third scan was obtained without the stimulation of drug cues, which was used as a measure of baseline brain metabolic activity. We hypothesized that if cognitive inhibition of craving occurred, then it would be accompanied by decreases in metabolic activity in NAcc (in which activity is associated with prediction of reward) and in OFC (in which activity is related to motivational value of conditioned cues). We also assessed if the inhibition in these brain regions was associated by activation of the right inferior frontal cortex (Brodmann area 44), which is a critical brain region for exerting inhibitory control (Aron et al., 2004).