D2 autoreceptors gate vulnerability to cocaine use disorder

Murray, E. M.; Diaz-Urbina, D.; Ventriglia, E.; Tischer, A.; Shin, J. H.; Lee, S.-A.; Anderson, L. G.; Cerveny, S.; Bleimeister, I.; Bocarsly, M. E.; Michaelides, M.; Alvarez, V. A.

doi:10.64898/2026.03.10.710882

bioRxiv · 10.64898/2026.03.10.710882

D2 autoreceptors gate vulnerability to cocaine use disorder

Murray, E. M.·Diaz-Urbina, D.·Ventriglia, E.·Tischer, A.·Shin, J. H.·Lee, S.-A.·Anderson, L. G.·Cerveny, S.·Bleimeister, I.·Bocarsly, M. E.·Michaelides, M.·Alvarez, V. A.

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Abstract

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 use2-5, 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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Murray, E. M., Diaz-Urbina, D., Ventriglia, E., Tischer, A., Shin, J. H., Lee, S.-A., Anderson, L. G., Cerveny, S., Bleimeister, I., Bocarsly, M. E., Michaelides, M., Alvarez, V. A.. 2026-03-11. D2 autoreceptors gate vulnerability to cocaine use disorder. https://doi.org/10.64898/2026.03.10.710882

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