Effects of depressive symptoms and peripheral DAT methylation on neural reactivity to alcohol cues in alcoholism

Abstract

In alcohol-dependent (AD) patients, alcohol cues induce strong activations in brain areas associated with alcohol craving and relapse, such as the nucleus accumbens (NAc) and amygdala. However, little is known about the influence of depressive symptoms, which are common in AD patients, on the brain's reactivity to alcohol cues. The methylation state of the dopamine transporter gene (DAT) has been associated with alcohol dependence, craving and depression, but its influence on neural alcohol cue reactivity has not been tested. Here, we compared brain reactivity to alcohol cues in 38 AD patients and 17 healthy controls (HCs) using functional magnetic resonance imaging and assessed the influence of depressive symptoms and peripheral DAT methylation in these responses. We show that alcoholics with low Beck's Depression Inventory scores (n=29) had higher cue-induced reactivity in NAc and amygdala than those with mild/moderate depression scores (n=9), though subjective perception of craving was higher in those with mild/moderate depression scores. We corroborated a higher DAT methylation in AD patients than HCs, and showed higher DAT methylation in AD patients with mild/moderate than low depression scores. Within the AD cohort, higher methylation predicted craving and, at trend level (P=0.095), relapse 1 year after abstinence. Finally, we show that amygdala cue reactivity correlated with craving and DAT methylation only in AD patients with low depression scores. These findings suggest that depressive symptoms and DAT methylation are associated with alcohol craving and associated brain processes in alcohol dependence, which may have important consequences for treatment. Moreover, peripheral DAT methylation may be a clinically relevant biomarker in AD patients.

Figure 1

(a) Mean peripheral DAT promoter methylation in AD patients and HCs (mean%±s.d.). AD patients had elevated DAT methylation compared with HCs (P=0.008). (b) DAT methylation predicted DAQ craving in AD patients (r²=0.14, P=0.024), whereas not in HCs (r²=0.043, P=0.43). When comparing regression slopes between these groups, the AD group showed a stronger correlation between DAT methylation and DAQ craving than HCs (Fisher’s z=1.88, P=0.03). AD, alcohol-dependent; DAQ, Desire for Alcohol Questionnaire; DAT, dopamine transporter gene; HC, healthy control.

Figure 2

AD patients with low depression scores had stronger alcohol cue reactivity in the bilateral NAc (P=0.046; a) and bilateral amygdala (P=0.01; b) compared with AD patients with moderate/high depression scores. Regions of interest were anatomically defined. There were no group differences between AD patients (both groups pooled together, n=38) and HCs (n=17) for alcohol cue-induced reactivity. AD, alcohol-dependent; HC, healthy control; NAc, nucleus accumbens.

Figure 3

DAQ craving correlated with neural alcohol cue reactivity in the bilateral amygdala in the AD group with low depression (depr) scores (r=0.48, P=0.008), but not in the group with mild/moderate depression scores (P>0.1). AD, alcohol-dependent; DAQ, Desire for Alcohol Questionnaire.