Murray et al - "D2 autoreceptors gate cocaine abuse vulnerability with discriminative marker of risk "

Published: 28 July 2026| Version 1 | DOI: 10.17632/3zwyv4grzz.1
Contributors:
, Daniel Diaz-Urbina, Roland Bock, Mike Michaelides, Veronica Alvarez

Description

Dataset for the manuscript Murray et al. published in Science Advances Summary: A defining feature of substance use disorder is that repeated drug use does not always lead to addiction, motivating the search for biomarkers of vulnerability1. Reduced striatal dopamine D2/3 receptor availability is a robust PET correlate of problematic stimulant use, but the signal may reflect high endogenous dopamine level, and it conflates presynaptic D2 autoreceptors on dopamine axons with postsynaptic D2/3 heteroreceptors on striatal projection neurons. We dissociated these contributions using cell type–specific Drd2 haploinsufficiency in dopamine neurons (autoD2KD), D2-expressing medium spiny neurons (MSN-D2KD), or both. Autoreceptor haploinsufficiency (autoD2KD) weakened presynaptic control of dopamine release, enhanced phasic gain, and prolonged cocaine-evoked dopamine elevations. This was accompanied by a hyper-exploratory trait and altered cocaine adaptation. Specifically, autoD2KD mice showed greater cocaine-seeking behavior, despite intact responses to sucrose reward and punishment. Although all genotypes showed graded reductions in striatal D2/3 binding, D1-like compensations diverged, resulting in different D1:D2/3 ratio in the striatum. The clinical implication is that striatal D1 density and D1:D2/3 balance may emerge as critical biomarkers for distinguishing cell-type-specific D2 reductions relevant to addiction vulnerability.

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methods and protocols were validated. data was reproduced by several experiments and often analyzed blind of condition.

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Striatum, Addictive Behavior, Dopamine Receptor

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