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Disrupting D1-NMDA or D2-NMDA receptor heteromerization prevents cocaine's rewarding effects but preserves natural reward processing. 2021
Andry Andrianarivelo, and
Estefani Saint-Jour, and
Paula Pousinha, and
Sebastian P Fernandez, and
Anna Petitbon, and
Veronique De Smedt-Peyrusse, and
Nicolas Heck, and
Vanesa Ortiz, and
Marie-Charlotte Allichon, and
Vincent Kappès, and
Sandrine Betuing, and
Roman Walle, and
Ying Zhu, and
Charlène Joséphine, and
Alexis-Pierre Bemelmans, and
Gustavo Turecki, and
Naguib Mechawar, and
Jonathan A Javitch, and
Jocelyne Caboche, and
Pierre Trifilieff, and
Jacques Barik, and
Peter Vanhoutte
CNRS, UMR 8246, Neuroscience Paris Seine, F-75005 Paris, France.
Addictive drugs increase dopamine in the nucleus accumbens (NAc), where it persistently shapes excitatory glutamate transmission and hijacks natural reward processing. Here, we provide evidence, from mice to humans, that an underlying mechanism relies on drug-evoked heteromerization of glutamate N-methyl-d-aspartate receptors (NMDAR) with dopamine receptor 1 (D1R) or 2 (D2R). Using temporally controlled inhibition of D1R-NMDAR heteromerization, we unraveled their selective implication in early phases of cocaine-mediated synaptic, morphological, and behavioral responses. In contrast, preventing D2R-NMDAR heteromerization blocked the persistence of these adaptations. Interfering with these heteromers spared natural reward processing. Notably, we established that D2R-NMDAR complexes exist in human samples and showed that, despite a decreased D2R protein expression in the NAc, individuals with psychostimulant use disorder display a higher proportion of D2R forming heteromers with NMDAR. These findings contribute to a better understanding of molecular mechanisms underlying addiction and uncover D2R-NMDAR heteromers as targets with potential therapeutic value.
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