TY - JOUR
T1 - Disrupting D1-NMDA or D2-NMDA receptor heteromerization prevents cocaine's rewarding effects but preserves natural reward processing
AU - Andrianarivelo, Andry
AU - Saint-Jour, Estefani
AU - Pousinha, Paula
AU - Fernandez, Sebastian P.
AU - Petitbon, Anna
AU - De Smedt-Peyrusse, Veronique
AU - Heck, Nicolas
AU - Ortiz, Vanesa
AU - Allichon, Marie Charlotte
AU - Kappès, Vincent
AU - Betuing, Sandrine
AU - Walle, Roman
AU - Zhu, Ying
AU - Joséphine, Charlène
AU - Bemelmans, Alexis Pierre
AU - Turecki, Gustavo
AU - Mechawar, Naguib
AU - Javitch, Jonathan A.
AU - Caboche, Jocelyne
AU - Trifilieff, Pierre
AU - Barik, Jacques
AU - Vanhoutte, Peter
N1 - Publisher Copyright:
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.
PY - 2021/10
Y1 - 2021/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85117855179&partnerID=8YFLogxK
U2 - 10.1126/sciadv.abg5970
DO - 10.1126/sciadv.abg5970
M3 - Article
C2 - 34669474
AN - SCOPUS:85117855179
SN - 2375-2548
VL - 7
JO - Science advances
JF - Science advances
IS - 43
M1 - eabg5970
ER -