Monoamine polygenic liability in health and cocaine dependence: Imaging genetics study of aversive processing and associations with depression symptomatology

Background: Gene polymorphisms that affect serotonin signaling modulate reactivity to salient stimuli and risk for emotional disturbances. Here, we hypothesized that these serotonin genes, which have been primarily explored in depressive disorders, could also have important implications for drug addiction, with the potential to reveal important insights into drug symptomatology, severity, and/or possible sequelae such as dysphoria. Methods: Using an imaging genetics approach, the current study tested in 62 cocaine abusers and 57 healthy controls the separate and combined effects of variations in the serotonin transporter (5- HTTLPR) and monoamine oxidase A (MAOA) genes on processing of aversive information. Reactivity to standardized unpleasant images was indexed by a psychophysiological marker of stimulus salience (i.e., the late positive potential (LPP) component of the event-related potential) during passive picture viewing. Depressive symptomatology was assessed with the Beck Depression Inventory (BDI). Results: Results showed that, independent of diagnosis, the highest unpleasant LPPs emerged in individuals with MAOA-Low and at least one 'Short' allele of 5- HTTLPR. Uniquely in the cocaine participants with these two risk variants, higher unpleasant LPPs correlated with higher BDI scores. Conclusions: Taken together, these results suggest that a multilocus genetic composite of monoamine signaling relates to depression symptomatology through brain function associated with the experience of negative emotions. This research lays the groundwork for future studies that can investigate clinical outcomes and/or pharmacogenetic therapies in drug addiction and potentially other psychopathologies of emotion dysregulation.