Mesocorticolimbic function in cocaine polydrug users: A multimodal study of drug cue reactivity and cognitive regulation

Addictions are thought to be fostered by the emergence of poorly regulated mesocorticolimbic responses to drug-related cues. The development and persistence of these responses might be promoted by altered glutamate transmission, including changes to type 5 metabotropic glutamate receptors (mGluR5s). Unknown, however, is when these changes arise and whether the mGluR5 and mesocorticolimbic alterations are related. To investigate, non-dependent cocaine polydrug users and cocaine-naive healthy controls underwent a positron emission tomography scan (15 cocaine users and 14 healthy controls) with [11C]ABP688, and a functional magnetic resonance imaging scan (15/group) while watching videos depicting activities with and without cocaine use. For some drug videos, participants were instructed to use a cognitive strategy to lower craving. Both groups exhibited drug cue-induced mesocorticolimbic activations and these were larger in the cocaine polydrug users than healthy controls during the session's second half. During the cognitive regulation trials, the cocaine users' corticostriatal responses were reduced. [11C]ABP688 binding was unaltered in cocaine users, relative to healthy controls, but post hoc analyses found reductions in those with 75 or more lifetime cocaine use sessions. Finally, among cocaine users (n = 12), individual differences in prefrontal [11C]ABP688 binding were associated with midbrain and limbic region activations during the regulation trials. Together, these preliminary findings raise the possibility that (i) recreational polydrug cocaine users show biased brain processes towards cocaine-related cues and (ii) repeated cocaine use can lower cortical mGluR5 levels, diminishing the ability to regulate drug cue responses. These alterations might promote susceptibility to addiction and identify early intervention targets. Recreational cocaine users underwent functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) to measure drug cue reactivity and mGlu5 receptor availability. Compared to control participants, cocaine users displayed greater relative mesocorticolimbic activations to drug cues whereas mGlu5 receptor availability was lower only in those who had used cocaine more than 75 times. Lower prefrontal mGluR5 availability was associated with higher subcortical drug cue responses during craving regulation trials. Together, these results suggest that accumulating cocaine use might reduce cortical mGluR5 contributing to impaired cognitive control.image