期刊
SCIENCE ADVANCES
卷 7, 期 43, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abg5970
关键词
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资金
- CNRS
- INSERM
- Sorbonne Universite, Faculte des Sciences et Ingenierie
- Universite de Bordeaux
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (INRAE)
- Universite Cote d'Azur
- Agence Nationale pour la Recherche (ANR) [ANR-15-CE16-001, ANR-18-CE37-0003-02, ANR-10-IDEX-03-02, ANR-16-CE16-0022]
- Fondation pour la Recherche Medicale (FRM) [DPA20140629798, DEQ20180339159]
- Institut de Recherche en Sante publique (IReSP) Aviesan APP-addiction 2019
- NARSAD Young Investigator Grants from the Brain and Behavior Foundation
- BioPsy LabEx excellence cluster
- LabEx BRAIN
- NIH [MH54137]
- Hope for Depression Research Foundation
- RQSHA
- HBHL (CFREF)
- French Ministry of Research
- Ecole Universitaire de Recherche (EUR Neuro, Bordeaux Neurocampus)
- FRM
- Agence Nationale de la Recherche (ANR) [ANR-18-CE37-0003] Funding Source: Agence Nationale de la Recherche (ANR)
The study reveals that addictive drugs induce heteromerization of dopamine receptors with glutamate NMDA receptors, playing a key role in cocaine-induced adaptive changes. Blocking the formation of heteromers between dopamine receptor D2R and NMDA receptor can prevent the persistence of these adaptive changes.
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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