Mesocorticolimbic Dopamine-Reward Tract Alterations and the ‘Dark Side’ of Methamphetamine Addiction

Abstract

Mesocorticolimbic circuits are central to theories of methamphetamine and other addictions. White-matter fibres are a necessary component of those circuits. However, the extent to which mesocorticolimbic white-matter tracts are altered in methamphetamine addiction is unknown. The current study addressed this gap as well as sought to determine relationships with neurofunctional and behavioural deficits concerning nondrug rewards. Multimodal MRI was acquired from 92 people with problematic methamphetamine-use experience (MA⁺) and 98 methamphetamine-naïve controls (MA⁻). Diffusion tractography mapped probabilistic fibre paths connecting midbrain presynaptic dopamine hubs to striatal and medial orbitofrontal areas highly sensitive to rewards. MA⁺ exhibited microstructural alterations (via fractional anisotropy [FA]) along this mesocorticolimbic tract—in particular, white-matter segments running through anterior limb of the internal capsule (ALIC_FA: MA⁺ > MA⁻) and near the medial orbitofrontal target area (mOFC_FA: MA⁺ < MA⁻). In addition, task-fMRI revealed that MA⁺ exhibited reduced activations to monetary rewards within the striatal and mOFC area versus MA⁻. Moreover, MA⁺ participants reported they attributed lower hedonic value and lesser motivational salience to broader nondrug rewards/pleasant experiences relative to MA⁻. Further, within MA⁺ participants, those exhibiting decreased ALIC_FA or mOFC_FA reported attributing lower hedonic value to nondrug rewards/experiences relative to their peers—with a similar correlation found for ALIC_FA and motivational-salience reports. Our findings identified microstructural alterations in a mesocorticolimbic white-matter tract plausibly supporting reward-related dopaminergic signalling in people experienced with methamphetamine. Such alterations may play a role in the lower valuation of nondrug rewards and diminished motivation to pursue typical/nondrug activities associated with methamphetamine use.