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

C E Wiers,H Walter,N D Volkow,J Lindenmeyer,F Bermpohl,E Shumay,A Kotsiari,H Frieling

doi:10.1038/tp.2015.141

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.

Highlights

Alcohol dependence is a chronic relapsing disorder, characterized by continued drinking despite an awareness of negative consequences
Neuroimaging studies have shown that alcohol cues evoke strong responses in mesolimbic brain areas in alcoholdependent (AD) patients, including the nucleus accumbens (NAc) and amygdala, which are associated with craving,[4,5] and relapse after abstinence.[6,7,8]
As the DAT1 9 R allele has been associated with reduced DA transporter 1 (DAT) expression,[17] it may be that the allele leads to accumulation of synaptic DA, which results in increased reward processing

Summary

Introduction

Alcohol dependence is a chronic relapsing disorder, characterized by continued drinking despite an awareness of negative consequences. People often start drinking because of the rewarding, hedonic effects of alcohol, which are induced by dopamine (DA) release in the nucleus accumbens (NAc).[1,2] With repeated exposure to alcohol, the cues associated with it (for example, the sight of a bar or beer bottle) become conditioned over the course of addiction These cues, lead to DA increases in mesolimbic reward pathways, thereby acting as a ‘motivational magnet’ and triggering alcohol consumption.[3] neuroimaging studies have shown that alcohol cues evoke strong responses in mesolimbic brain areas in alcoholdependent (AD) patients, including the NAc and amygdala, which are associated with craving,[4,5] and relapse after abstinence.[6,7,8].

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