Disrupting D1-NMDA or D2-NMDA receptor heteromerization prevents cocaine’s rewarding effects but preserves natural reward processing
Andry Andrianarivelo, Estefani Saint‐Jour, Paula A. Pousinha, Sebastián P. Fernández, Anna Petitbon, Véronique De Smedt‐Peyrusse, Nicolas Heck, Vanesa Ortiz, Marie‐Charlotte Allichon, Vincent Kappès, Sandrine Bétuing, Roman Walle, Ying Zhu, Charlène Joséphine, Alexis‐Pierre Bemelmans, Gustavo Turecki, Naguib Mechawar, Jonathan A. Javitch, Jocelyne Caboche, Pierre Trifilieff, Jacques Barik, Peter Vanhoutte
Abstract
-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.