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Gray-matter volume, midbrain dopamine D2/D3 receptors and drug craving in methamphetamine users

Abstract

Dysfunction of the mesocorticolimbic system has a critical role in clinical features of addiction. Despite evidence suggesting that midbrain dopamine receptors influence amphetamine-induced dopamine release and that dopamine is involved in methamphetamine-induced neurotoxicity, associations between dopamine receptors and gray-matter volume have been unexplored in methamphetamine users. Here we used magnetic resonance imaging and [18F]fallypride positron emission tomography, respectively, to measure gray-matter volume (in 58 methamphetamine users) and dopamine D2/D3 receptor availability (binding potential relative to nondisplaceable uptake of the radiotracer, BPnd) (in 31 methamphetamine users and 37 control participants). Relationships between these measures and self-reported drug craving were examined. Although no difference in midbrain D2/D3 BPnd was detected between methamphetamine and control groups, midbrain D2/D3 BPnd was positively correlated with gray-matter volume in the striatum, prefrontal cortex, insula, hippocampus and temporal cortex in methamphetamine users, but not in control participants (group-by-midbrain D2/D3 BPnd interaction, P<0.05 corrected for multiple comparisons). Craving for methamphetamine was negatively associated with gray-matter volume in the insula, prefrontal cortex, amygdala, temporal cortex, occipital cortex, cerebellum and thalamus (P<0.05 corrected for multiple comparisons). A relationship between midbrain D2/D3 BPnd and methamphetamine craving was not detected. Lower midbrain D2/D3 BPnd may increase vulnerability to deficits in gray-matter volume in mesocorticolimbic circuitry in methamphetamine users, possibly reflecting greater dopamine-induced toxicity. Identifying factors that influence prefrontal and limbic volume, such as midbrain BPnd, may be important for understanding the basis of drug craving, a key factor in the maintenance of substance-use disorders.

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Acknowledgements

This research was supported by NIH Grants P20 DA022539, R01 DA015179, R01 DA020726 (EDL) and M01RR00865 (UCLA GCRC). Additional funding was provided by an endowment from the Thomas P and Katherine K Pike Chair in Addiction Studies and a gift from the Marjorie M Greene Trust. Drs Morales and Kohno were supported by F31 DA033117 and F31 DA033120, respectively, as well as T32 DA024635. None of the sponsors were involved with the design, collection, analysis or interpretation of data, writing the manuscript or the decision to submit the manuscript for publications.

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Morales, A., Kohno, M., Robertson, C. et al. Gray-matter volume, midbrain dopamine D2/D3 receptors and drug craving in methamphetamine users. Mol Psychiatry 20, 764–771 (2015). https://doi.org/10.1038/mp.2015.47

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