Table Info

Table 1.

Main techniques to assess receptor heteromerization

Method	Proximity/resolution	Sample type
Co-IP	N.A./sampled tissue	Lysed tissue
In situ hybridization	> 500 nm–1 µm	Heterologous system/native tissue
Immunogold	20–30 nm	Native tissue
PLA	16 nm (strand level)–40 nm (epitope level)	Native tissue/heterologous system
BRET	< 10 nm	Heterologous system
FRET	< 10 nm	Heterologous system
TR-FRET	< 10 nm	Heterologous system/native tissue/membrane preparations
SRET	< 10 nm	Heterologous system
AlphaLisa	< 200 nm	Membrane preparations
NanoBiT	N.D./low molecular weight of NanoLuc (19 kDa)	Heterologous system
SPT	100–300 nm Movement detection < 25 nm	Heterologous system/culture of neurons

N.A.: not applicable; N.D.: not determined; Co-IP: co-immunoprecipitation; PLA: proximity ligation assay; BRET: bioluminescence resonance energy transfer; FRET: fluorescence/Förster resonance energy transfer; TR-FRET: time-resolved FRET; SRET: sequential resonance energy transfer; SPT: single particle tracking

Declarations

Author contributions

AV, AP, and MCA: Writing—original draft. PT and PV: Conceptualization, Writing—review & editing.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Our research work was supported by the “Centre de la Recherche Scientifique” (CNRS), “l’institut National de la Santé et de la Recherche Médicale” (INSERM), “l’institut National de la Recherche pour l’agriculture et l’environnement” (INRAE), Sorbonne University and University of Bordeaux; University of Bordeaux’s IdEx “Investments for the future” program/[GPR BRAIN_2030] (PT), the “Agence Nationale pour le Recherche” (ANR) ANR-FrontoFat ([ANR-20-CE14-0020] to PT), ANR-Dropstress ([ANR-18-CE37-003] to PV), ANR-Striacode ([ANR-23-CE37-0006] to PV), Institut de Recherche en Santé publique (IReSP) Aviesan APP-addiction 2019 ([20II146-00] to PV and PT), IReSP Aviesan APP-addiction 2023 ([23IIsSP089] to PV and PT). AP is a recipient of a PhD fellowship from the “Ecole Universitaire de Recherche” (EUR Neuro, Bordeaux Neurocampus). AV is the recipient of a PhD fellowship from the French ministry of research, MCA is the recipient of 4th year PhD fellowship from the “Fondation pour la Recherche Médicale” (FRM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

References

Nestler EJ, Lüscher C. The Molecular Basis of Drug Addiction: Linking Epigenetic to Synaptic and Circuit Mechanisms. Neuron. 2019;102:48–59. [DOI] [PubMed] [PMC]

Salery M, Trifilieff P, Caboche J, Vanhoutte P. From Signaling Molecules to Circuits and Behaviors: Cell-Type-Specific Adaptations to Psychostimulant Exposure in the Striatum. Biol Psychiatry. 2020;87:944–53. [DOI] [PubMed]

Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A. 1988;85:5274–8. [DOI] [PubMed] [PMC]

Lüscher C, Malenka RC. Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling. Neuron. 2011;69:650–63. [DOI] [PubMed] [PMC]

Volkow ND, Morales M. The Brain on Drugs: From Reward to Addiction. Cell. 2015;162:712–25. [DOI] [PubMed]

Hyman SE, Malenka RC. Addiction and the brain: the neurobiology of compulsion and its persistence. Nat Rev Neurosci. 2001;2:695–703. [DOI] [PubMed]

Moss J, Bolam JP. A dopaminergic axon lattice in the striatum and its relationship with cortical and thalamic terminals. J Neurosci. 2008;28:11221–30. [DOI] [PubMed] [PMC]

Doig NM, Moss J, Bolam JP. Cortical and thalamic innervation of direct and indirect pathway medium-sized spiny neurons in mouse striatum. J Neurosci. 2010;30:14610–8. [DOI] [PubMed] [PMC]

Felder CC, Williams HL, Axelrod J. A transduction pathway associated with receptors coupled to the inhibitory guanine nucleotide binding protein Gi that amplifies ATP-mediated arachidonic acid release. Proc Natl Acad Sci U S A. 1991;88:6477–80. [DOI] [PubMed] [PMC]

10.

Corvol JC, Studler JM, Schonn JS, Girault JA, Hervé D. Galpha(olf) is necessary for coupling D1 and A2a receptors to adenylyl cyclase in the striatum. J Neurochem. 2001;76:1585–8. [DOI] [PubMed]

11.

Bertran-Gonzalez J, Bosch C, Maroteaux M, Matamales M, Hervé D, Valjent E, et al. Opposing patterns of signaling activation in dopamine D1 and D2 receptor-expressing striatal neurons in response to cocaine and haloperidol. J Neurosci. 2008;28:5671–85. [DOI] [PubMed] [PMC]

12.

Yao WD, Spealman RD, Zhang J. Dopaminergic signaling in dendritic spines. Biochem Pharmacol. 2008;75:2055–69. [DOI] [PubMed] [PMC]

13.

Durieux PF, Bearzatto B, Guiducci S, Buch T, Waisman A, Zoli M, et al. D2R striatopallidal neurons inhibit both locomotor and drug reward processes. Nat Neurosci. 2009;12:393–5. [DOI] [PubMed]

14.

Hikida T, Kimura K, Wada N, Funabiki K, Nakanishi S. Distinct roles of synaptic transmission in direct and indirect striatal pathways to reward and aversive behavior. Neuron. 2010;66:896–907. [DOI] [PubMed]

15.

Lobo MK, Covington HE 3rd, Chaudhury D, Friedman AK, Sun H, Damez-Werno D, et al. Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward. Science. 2010;330:385–90. [DOI] [PubMed] [PMC]

16.

Ferguson SM, Eskenazi D, Ishikawa M, Wanat MJ, Phillips PEM, Dong Y, et al. Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization. Nat Neurosci. 2011;14:22–4. [DOI] [PubMed] [PMC]

17.

Durieux PF, Schiffmann SN, d’Exaerde AdK. Differential regulation of motor control and response to dopaminergic drugs by D1R and D2R neurons in distinct dorsal striatum subregions. EMBO J. 2012;31:640–53. [DOI] [PubMed] [PMC]

18.

Bock R, Shin JH, Kaplan AR, Dobi A, Markey E, Kramer PF, et al. Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use. Nat Neurosci. 2013;16:632–8. [DOI] [PubMed] [PMC]

19.

Chandra R, Lenz JD, Gancarz AM, Chaudhury D, Schroeder GL, Han M, et al. Optogenetic inhibition of D1R containing nucleus accumbens neurons alters cocaine-mediated regulation of Tiam1. Front Mol Neurosci. 2013;6:13. [DOI] [PubMed] [PMC]

20.

Farrell MS, Pei Y, Wan Y, Yadav PN, Daigle TL, Urban DJ, et al. A Gα_s DREADD mouse for selective modulation of cAMP production in striatopallidal neurons. Neuropsychopharmacology. 2013;38:854–62. [DOI] [PubMed] [PMC]

21.

Calipari ES, Bagot RC, Purushothaman I, Davidson TJ, Yorgason JT, Peña CJ, et al. In vivo imaging identifies temporal signature of D1 and D2 medium spiny neurons in cocaine reward. Proc Natl Acad Sci U S A. 2016;113:2726–31. [DOI] [PubMed] [PMC]

22.

Pardo-Garcia TR, Garcia-Keller C, Penaloza T, Richie CT, Pickel J, Hope BT, et al. Ventral Pallidum Is the Primary Target for Accumbens D1 Projections Driving Cocaine Seeking. J Neurosci. 2019;39:2041–51. [DOI] [PubMed] [PMC]

23.

Burke DA, Rotstein HG, Alvarez VA. Striatal Local Circuitry: A New Framework for Lateral Inhibition. Neuron. 2017;96:267–84. [DOI] [PubMed] [PMC]

24.

Dobbs LK, Kaplan AR, Lemos JC, Matsui A, Rubinstein M, Alvarez VA. Dopamine Regulation of Lateral Inhibition between Striatal Neurons Gates the Stimulant Actions of Cocaine. Neuron. 2016;90:1100–13. [DOI] [PubMed] [PMC]

25.

Lobo MK, Nestler EJ. The striatal balancing act in drug addiction: distinct roles of direct and indirect pathway medium spiny neurons. Front Neuroanat. 2011;5:41. [DOI] [PubMed] [PMC]

26.

Girault JA, Valjent E, Caboche J, Hervé D. ERK2: a logical AND gate critical for drug-induced plasticity? Curr Opin Pharmacol. 2007;7:77–85. [DOI] [PubMed]

27.

Pascoli V, Besnard A, Hervé D, Pagès C, Heck N, Girault J, et al. Cyclic adenosine monophosphate-independent tyrosine phosphorylation of NR2B mediates cocaine-induced extracellular signal-regulated kinase activation. Biol Psychiatry. 2011;69:218–27. [DOI] [PubMed]

28.

Pascoli V, Cahill E, Bellivier F, Caboche J, Vanhoutte P. Extracellular signal-regulated protein kinases 1 and 2 activation by addictive drugs: a signal toward pathological adaptation. Biol Psychiatry. 2014;76:917–26. [DOI] [PubMed]

29.

Cahill E, Salery M, Vanhoutte P, Caboche J. Convergence of dopamine and glutamate signaling onto striatal ERK activation in response to drugs of abuse. Front Pharmacol. 2014;4:172. [DOI] [PubMed] [PMC]

30.

Wang M, Wong AH, Liu F. Interactions between NMDA and dopamine receptors: a potential therapeutic target. Brain Res. 2012;1476:154–63. [DOI] [PubMed]

31.

Andrianarivelo A, Saint-Jour E, Walle R, Trifilieff P, Vanhoutte P. Modulation and functions of dopamine receptor heteromers in drugs of abuse-induced adaptations. Neuropharmacology. 2019;152:42–50. [DOI] [PubMed]

32.

Missale C, Fiorentini C, Busi C, Collo G, Spano PF. The NMDA/D1 receptor complex as a new target in drug development. Curr Top Med Chem. 2006;6:801–8. [DOI] [PubMed]

33.

Ferré S, Quiroz C, Orru M, Guitart X, Navarro G, Cortés A, et al. Adenosine A_2A Receptors and A_2A Receptor Heteromers as Key Players in Striatal Function. Front Neuroanat. 2011;5:36. [DOI] [PubMed] [PMC]

34.

Fuxe K, Borroto-Escuela DO, Romero-Fernandez W, Palkovits M, Tarakanov AO, Ciruela F, et al. Moonlighting proteins and protein-protein interactions as neurotherapeutic targets in the G protein-coupled receptor field. Neuropsychopharmacology. 2014;39:131–55. [DOI] [PubMed] [PMC]

35.

Missale C, Fiorentini C, Collo G, Spano P. The neurobiology of dopamine receptors: evolution from the dual concept to heterodimer complexes. J Recept Signal Transduct Res. 2010;30:347–54. [DOI] [PubMed]

36.

Borroto-Escuela DO, Carlsson J, Ambrogini P, Narváez M, Wydra K, Tarakanov AO, et al. Understanding the Role of GPCR Heteroreceptor Complexes in Modulating the Brain Networks in Health and Disease. Front Cell Neurosci. 2017;11:37. [DOI] [PubMed] [PMC]

37.

Ferré S, Bonaventura J, Tomasi D, Navarro G, Moreno E, Cortés A, et al. Allosteric mechanisms within the adenosine A_2A-dopamine D₂ receptor heterotetramer. Neuropharmacology. 2016;104:154–60. [DOI] [PubMed] [PMC]

38.

Lee FJS, Xue S, Pei L, Vukusic B, Chéry N, Wang Y, et al. Dual regulation of NMDA receptor functions by direct protein-protein interactions with the dopamine D1 receptor. Cell. 2002;111:219–30. [DOI] [PubMed]

39.

Pei L, Lee FJS, Moszczynska A, Vukusic B, Liu F. Regulation of dopamine D1 receptor function by physical interaction with the NMDA receptors. J Neurosci. 2004;24:1149–58. [DOI] [PubMed] [PMC]

40.

Cepeda C, Levine MS. Where do you think you are going? The NMDA-D1 receptor trap. Sci STKE. 2006;2006:pe20. [DOI] [PubMed]

41.

Ladepeche L, Dupuis JP, Bouchet D, Doudnikoff E, Yang L, Campagne Y, et al. Single-molecule imaging of the functional crosstalk between surface NMDA and dopamine D1 receptors. Proc Natl Acad Sci U S A. 2013;110:18005–10. [DOI] [PubMed] [PMC]

42.

Dale NC, Johnstone EKM, Pfleger KDG. GPCR heteromers: An overview of their classification, function and physiological relevance. Front Endocrinol (Lausanne). 2022;13:931573. [DOI] [PubMed] [PMC]

43.

Ferré S, Baler R, Bouvier M, Caron MG, Devi LA, Durroux T, et al. Building a new conceptual framework for receptor heteromers. Nat Chem Biol. 2009;5:131–4. [DOI] [PubMed] [PMC]

44.

Gomes I, Ayoub MA, Fujita W, Jaeger WC, Pfleger KDG, Devi LA. G Protein-Coupled Receptor Heteromers. Annu Rev Pharmacol Toxicol. 2016;56:403–25. [DOI] [PubMed] [PMC]

45.

Fernández-Dueñas V, Bonaventura J, Aso E, Luján R, Ferré S, Ciruela F. Overcoming the Challenges of Detecting GPCR Oligomerization in the Brain. Curr Neuropharmacol. 2022;20:1035–45. [DOI] [PubMed] [PMC]

46.

Förster T. Energy migration and fluorescence. J Biomed Opt. 2012;17:011002. [DOI] [PubMed]

47.

Angers S, Salahpour A, Joly E, Hilairet S, Chelsky D, Dennis M, et al. Detection of beta 2-adrenergic receptor dimerization in living cells using bioluminescence resonance energy transfer (BRET). Proc Natl Acad Sci U S A. 2000;97:3684–9. [DOI] [PubMed] [PMC]

48.

Milligan G, Ramsay D, Pascal G, Carrillo JJ. GPCR dimerisation. Life Sci. 2003;74:181–8. [DOI] [PubMed]

49.

Overton MC, Blumer KJ. G-protein-coupled receptors function as oligomers in vivo. Curr Biol. 2000;10:341–4. [DOI] [PubMed]

50.

Wouters E, Vasudevan L, Crans RAJ, Saini DK, Stove CP. Luminescence- and Fluorescence-Based Complementation Assays to Screen for GPCR Oligomerization: Current State of the Art. Int J Mol Sci. 2019;20:2958. [DOI] [PubMed] [PMC]

51.

Crans RAJ, Wouters E, Valle-León M, Taura J, Massari CM, Fernández-Dueñas V, et al. Striatal Dopamine D₂-Muscarinic Acetylcholine M₁ Receptor-Receptor Interaction in a Model of Movement Disorders. Front Pharmacol. 2020;11:194. [DOI] [PubMed] [PMC]

52.

Wouters E, Marín AR, Dalton JAR, Giraldo J, Stove C. Distinct Dopamine D₂ Receptor Antagonists Differentially Impact D₂ Receptor Oligomerization. Int J Mol Sci. 2019;20:1686. [DOI] [PubMed] [PMC]

53.

Navarro G, McCormick PJ, Mallol J, Lluís C, Franco R, Cortés A, et al. Detection of receptor heteromers involving dopamine receptors by the sequential BRET-FRET technology. Methods Mol Biol. 2013;964:95–105. [DOI] [PubMed] [PMC]

54.

Albizu L, Cottet M, Kralikova M, Stoev S, Seyer R, Brabet I, et al. Time-resolved FRET between GPCR ligands reveals oligomers in native tissues. Nat Chem Biol. 2010;6:587–94. [DOI] [PubMed] [PMC]

55.

Cottet M, Faklaris O, Maurel D, Scholler P, Doumazane E, Trinquet E, et al. BRET and Time-resolved FRET strategy to study GPCR oligomerization: from cell lines toward native tissues. Front Endocrinol (Lausanne). 2012;3:92. [DOI] [PubMed] [PMC]

56.

Fernández-Dueñas V, Taura JJ, Cottet M, Gómez-Soler M, López-Cano M, Ledent C, et al. Untangling dopamine-adenosine receptor-receptor assembly in experimental parkinsonism in rats. Dis Model Mech. 2015;8:57–63. [DOI] [PubMed] [PMC]

57.

Mathis G. Probing molecular interactions with homogeneous techniques based on rare earth cryptates and fluorescence energy transfer. Clin Chem. 1995;41:1391–7. [PubMed]

58.

Butler C, Saraceno GE, Kechkar A, Bénac N, Studer V, Dupuis JP, et al. Multi-Dimensional Spectral Single Molecule Localization Microscopy. Front Bioinform. 2022;2:813494. [DOI] [PubMed] [PMC]

59.

Bénac N, Ezequiel Saraceno G, Butler C, Kuga N, Nishimura Y, Yokoi T, et al. Non-canonical interplay between glutamatergic NMDA and dopamine receptors shapes synaptogenesis. Nat Commun. 2024;15:27. [DOI] [PubMed] [PMC]

60.

Aloisi E, Le Corf K, Dupuis J, Zhang P, Ginger M, Labrousse V, et al. Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice. Nat Commun. 2017;8:1103. [DOI] [PubMed] [PMC]

61.

Mikasova L, De Rossi P, Bouchet D, Georges F, Rogemond V, Didelot A, et al. Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis. Brain. 2012;135:1606–21. [DOI] [PubMed]

62.

Cabello N, Gandía J, Bertarelli DCG, Watanabe M, Lluís C, Franco R, et al. Metabotropic glutamate type 5, dopamine D₂ and adenosine A_2a receptors form higher-order oligomers in living cells. J Neurochem. 2009;109:1497–507. [DOI] [PubMed] [PMC]

63.

Fredriksson S, Gullberg M, Jarvius J, Olsson C, Pietras K, Gústafsdóttir SM, et al. Protein detection using proximity-dependent DNA ligation assays. Nat Biotechnol. 2002;20:473–7. [DOI] [PubMed]

64.

Borroto-Escuela DO, Romero-Fernandez W, Garriga P, Ciruela F, Narvaez M, Tarakanov AO, et al. G protein-coupled receptor heterodimerization in the brain. Methods Enzymol. 2013;521:281–94. [DOI] [PubMed]

65.

Söderberg O, Leuchowius KJ, Gullberg M, Jarvius M, Weibrecht I, Larsson LG, et al. Characterizing proteins and their interactions in cells and tissues using the in situ proximity ligation assay. Methods. 2008;45:227–32. [DOI] [PubMed]

66.

Trifilieff P, Rives M, Urizar E, Piskorowski RA, Vishwasrao HD, Castrillon J, et al. Detection of antigen interactions ex vivo by proximity ligation assay: endogenous dopamine D2-adenosine A2A receptor complexes in the striatum. Biotechniques. 2011;51:111–8. [DOI] [PubMed] [PMC]

67.

Andrianarivelo A, Saint-Jour E, Pousinha P, Fernandez SP, Petitbon A, Smedt-Peyrusse VD, et al. Disrupting D1-NMDA or D2-NMDA receptor heteromerization prevents cocaine’s rewarding effects but preserves natural reward processing. Sci Adv. 2021;7:eabg5970. [DOI] [PubMed] [PMC]

68.

Cahill E, Pascoli V, Trifilieff P, Savoldi D, Kappès V, Lüscher C, et al. D1R/GluN1 complexes in the striatum integrate dopamine and glutamate signalling to control synaptic plasticity and cocaine-induced responses. Mol Psychiatry. 2014;19:1295–304. [DOI] [PubMed] [PMC]

69.

Zhu Y, Mészáros J, Walle R, Fan R, Sun Z, Dwork AJ, et al. Detecting G protein-coupled receptor complexes in postmortem human brain with proximity ligation assay and a Bayesian classifier. Biotechniques. 2020;68:122–9. [DOI] [PubMed] [PMC]

70.

Raykova D, Kermpatsou D, Malmqvist T, Harrison PJ, Sander MR, Stiller C, et al. A method for Boolean analysis of protein interactions at a molecular level. Nat Commun. 2022;13:4755. [DOI] [PubMed] [PMC]

71.

Rivas-Santisteban R, Rico AJ, Muñoz A, Rodríguez-Pérez AI, Reyes-Resina I, Navarro G, et al. Boolean analysis shows a high proportion of dopamine D₂ receptors interacting with adenosine A_2A receptors in striatal medium spiny neurons of mouse and non-human primate models of Parkinson’s disease. Neurobiol Dis. 2023;188:106341. [DOI] [PubMed]

72.

Fernández-Dueñas V, Gómez-Soler M, Valle-León M, Watanabe M, Ferrer I, Ciruela F. Revealing Adenosine A_2A-Dopamine D₂ Receptor Heteromers in Parkinson’s Disease Post-Mortem Brain through a New AlphaScreen-Based Assay. Int J Mol Sci. 2019;20:3600. [DOI] [PubMed] [PMC]

73.

Valle-León M, Callado LF, Aso E, Cajiao-Manrique MM, Sahlholm K, López-Cano M, et al. Decreased striatal adenosine A_2A-dopamine D₂ receptor heteromerization in schizophrenia. Neuropsychopharmacology. 2021;46:665–72. [DOI] [PubMed] [PMC]

74.

Lau CG, Zukin RS. NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nat Rev Neurosci. 2007;8:413–26. [DOI] [PubMed]

75.

Paoletti P, Bellone C, Zhou Q. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci. 2013;14:383–400. [DOI] [PubMed]

76.

Omkumar RV, Kiely MJ, Rosenstein AJ, Min KT, Kennedy MB. Identification of a phosphorylation site for calcium/calmodulindependent protein kinase II in the NR2B subunit of the N-methyl-D-aspartate receptor. J Biol Chem. 1996;271:31670–8. [DOI] [PubMed]

77.

Liao GY, Wagner DA, Hsu MH, Leonard JP. Evidence for direct protein kinase-C mediated modulation of N-methyl-D-aspartate receptor current. Mol Pharmacol. 2001;59:960–4. [DOI] [PubMed]

78.

Lieberman DN, Mody I. Regulation of NMDA channel function by endogenous Ca²⁺-dependent phosphatase. Nature. 1994;369:235–9. [DOI] [PubMed]

79.

Jin D, Xue B, Mao L, Wang JQ. Metabotropic glutamate receptor 5 upregulates surface NMDA receptor expression in striatal neurons via CaMKII. Brain Res. 2015;1624:414–23. [DOI] [PubMed] [PMC]

80.

Woods AS, Ciruela F, Fuxe K, Agnati LF, Lluis C, Franco R, et al. Role of electrostatic interaction in receptor-receptor heteromerization. J Mol Neurosci. 2005;26:125–32. [DOI] [PubMed]

81.

Ciruela F, Burgueño J, Casadó V, Canals M, Marcellino D, Goldberg SR, et al. Combining mass spectrometry and pull-down techniques for the study of receptor heteromerization. Direct epitope-epitope electrostatic interactions between adenosine A_2A and dopamine D₂ receptors. Anal Chem. 2004;76:5354–63. [DOI] [PubMed]

82.

Fiorentini C, Gardoni F, Spano P, Luca MD, Missale C. Regulation of dopamine D₁ receptor trafficking and desensitization by oligomerization with glutamate N-methyl-D-aspartate receptors. J Biol Chem. 2003;278:20196–202. [DOI] [PubMed]

83.

Scott L, Zelenin S, Malmersjö S, Kowalewski JM, Markus EZ, Nairn AC, et al. Allosteric changes of the NMDA receptor trap diffusible dopamine 1 receptors in spines. Proc Natl Acad Sci U S A. 2006;103:762–7. [DOI] [PubMed] [PMC]

84.

Zhang J, Xu TX, Hallett PJ, Watanabe M, Grant SG, Isacson O, et al. PSD-95 uncouples dopamine-glutamate interaction in the D₁/PSD-95/NMDA receptor complex. J Neurosci. 2009;29:2948–60. [DOI] [PubMed] [PMC]

85.

Ortinski PI, Turner JR, Pierce RC. Extrasynaptic targeting of NMDA receptors following D1 dopamine receptor activation and cocaine self-administration. J Neurosci. 2013;33:9451–61. [DOI] [PubMed] [PMC]

86.

Flores-Hernández J, Cepeda C, Hernández-Echeagaray E, Calvert CR, Jokel ES, Fienberg AA, et al. Dopamine enhancement of NMDA currents in dissociated medium-sized striatal neurons: role of D1 receptors and DARPP-32. J Neurophysiol. 2002;88:3010–20. [DOI] [PubMed]

87.

Wittmann M, Marino MJ, Henze DA, Seabrook GR, Conn PJ. Clozapine potentiation of N-methyl-D-aspartate receptor currents in the nucleus accumbens: role of NR2B and protein kinase A/Src kinases. J Pharmacol Exp Ther. 2005;313:594–603. [DOI] [PubMed]

88.

Nai Q, Li S, Wang SH, Liu J, Lee FJ, Frankland PW, et al. Uncoupling the D1-N-methyl-D-aspartate (NMDA) receptor complex promotes NMDA-dependent long-term potentiation and working memory. Biol Psychiatry. 2010;67:246–54. [DOI] [PubMed]

89.

Liu XY, Chu XP, Mao LM, Wang M, Lan HX, Li MH, et al. Modulation of D2R-NR2B interactions in response to cocaine. Neuron. 2006;52:897–909. [DOI] [PubMed]

90.

Higley MJ, Sabatini BL. Competitive regulation of synaptic Ca²⁺ influx by D2 dopamine and A2A adenosine receptors. Nat Neurosci. 2010;13:958–66. [DOI] [PubMed] [PMC]

91.

Robinson TE, Berridge KC. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev. 1993;18:247–91. [DOI] [PubMed]

92.

Hallett PJ, Spoelgen R, Hyman BT, Standaert DG, Dunah AW. Dopamine D1 activation potentiates striatal NMDA receptors by tyrosine phosphorylation-dependent subunit trafficking. J Neurosci. 2006;26:4690–700. [DOI] [PubMed] [PMC]

93.

Li A, Li W, Ali T, Yang C, Liu Z, Gao R, et al. A novel dopamine D2 receptor-NR2B protein complex might contribute to morphine use disorders. Eur J Pharmacol. 2023;961:176174. [DOI] [PubMed]

94.

Fuxe K, Marcellino D, Borroto-Escuela DO, Guescini M, Fernández-Dueñas V, Tanganelli S, et al. Adenosine-dopamine interactions in the pathophysiology and treatment of CNS disorders. CNS Neurosci Ther. 2010;16:e18–42. [DOI] [PubMed] [PMC]

95.

Cortés A, Casadó-Anguera V, Moreno E, Casadó V. The heterotetrameric structure of the adenosine A₁-dopamine D₁ receptor complex: Pharmacological implication for restless legs syndrome. Adv Pharmacol. 2019;84:37–78. [DOI] [PubMed]

96.

Svenningsson P, Le Moine C, Fisone G, Fredholm BB. Distribution, biochemistry and function of striatal adenosine A2A receptors. Prog Neurobiol. 1999;59:355–96. [DOI] [PubMed]

97.

Schiffmann SN, Fisone G, Moresco R, Cunha RA, Ferré S. Adenosine A_2A receptors and basal ganglia physiology. Prog Neurobiol. 2007;83:277–92. [DOI] [PubMed] [PMC]

98.

Domenici MR, Ferrante A, Martire A, Chiodi V, Pepponi R, Tebano MT, et al. Adenosine A_2A receptor as potential therapeutic target in neuropsychiatric disorders. Pharmacol Res. 2019;147:104338. [DOI] [PubMed]

99.

Kaster MP, Machado NJ, Silva HB, Nunes A, Ardais AP, Santana M, et al. Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress. Proc Natl Acad Sci U S A. 2015;112:7833–8. [DOI] [PubMed] [PMC]

100.

Fuxe K, Ungerstedt U. Action of caffeine and theophyllamine on supersensitive dopamine receptors: considerable enhancement of receptor response to treatment with DOPA and dopamine receptor agonists. Med Biol. 1974;52:48–54. [PubMed]

101.

Ferre S, von Euler G, Johansson B, Fredholm BB, Fuxe K. Stimulation of high-affinity adenosine A2 receptors decreases the affinity of dopamine D2 receptors in rat striatal membranes. Proc Natl Acad Sci U S A. 1991;88:7238–41. [DOI] [PubMed] [PMC]

102.

Hillion J, Canals M, Torvinen M, Casado V, Scott R, Terasmaa A, et al. Coaggregation, cointernalization, and codesensitization of adenosine A2A receptors and dopamine D2 receptors. J Biol Chem. 2002;277:18091–7. [DOI] [PubMed]

103.

Kamiya T, Saitoh O, Yoshioka K, Nakata H. Oligomerization of adenosine A_2A and dopamine D₂ receptors in living cells. Biochem Biophys Res Commun. 2003;306:544–9. [DOI] [PubMed]

104.

Canals M, Marcellino D, Fanelli F, Ciruela F, Benedetti Pd, Goldberg SR, et al. Adenosine A_2A-dopamine D₂ receptor-receptor heteromerization: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer. J Biol Chem. 2003;278:46741–9. [DOI] [PubMed]

105.

Canals M, Burgueño J, Marcellino D, Cabello N, Canela EI, Mallol J, et al. Homodimerization of adenosine A2A receptors: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer. J Neurochem. 2004;88:726–34. [DOI] [PubMed]

106.

Borroto-Escuela DO, Romero-Fernandez W, Tarakanov AO, Gómez-Soler M, Corrales F, Marcellino D, et al. Characterization of the A2AR-D₂R interface: focus on the role of the C-terminal tail and the transmembrane helices. Biochem Biophys Res Commun. 2010;402:801–7. [DOI] [PubMed]

107.

He Y, Li Y, Chen M, Pu Z, Zhang F, Chen L, et al. Habit Formation after Random Interval Training Is Associated with Increased Adenosine A_2A Receptor and Dopamine D₂ Receptor Heterodimers in the Striatum. Front Mol Neurosci. 2016;9:151. [DOI] [PubMed] [PMC]

108.

Borroto-Escuela DO, Narváez M, Wydra K, Pintsuk J, Pinton L, Jimenez-Beristain A, et al. Cocaine self-administration specifically increases A2AR-D2R and D2R-sigma1R heteroreceptor complexes in the rat nucleus accumbens shell. Relevance for cocaine use disorder. Pharmacol Biochem Behav. 2017;155:24–31. [DOI] [PubMed]

109.

Bonaventura J, Navarro G, Casadó-Anguera V, Azdad K, Rea W, Moreno E, et al. Allosteric interactions between agonists and antagonists within the adenosine A_2A receptor-dopamine D₂ receptor heterotetramer. Proc Natl Acad Sci U S A. 2015;112:E3609–18. [DOI] [PubMed] [PMC]

110.

Zhu Y, Dwork AJ, Trifilieff P, Javitch JA. Detection of G Protein-Coupled Receptor Complexes in Postmortem Human Brain by Proximity Ligation Assay. Curr Protoc Neurosci. 2020;91:e86. [DOI] [PubMed] [PMC]

111.

Navarro G, Cordomí A, Casadó-Anguera V, Moreno E, Cai N, Cortés A, et al. Evidence for functional pre-coupled complexes of receptor heteromers and adenylyl cyclase. Nat Commun. 2018;9:1242. [DOI] [PubMed] [PMC]

112.

Ferré S, Bonaventura J, Zhu W, Hatcher-Solis C, Taura J, Quiroz C, et al. Essential Control of the Function of the Striatopallidal Neuron by Pre-coupled Complexes of Adenosine A_2A-Dopamine D₂ Receptor Heterotetramers and Adenylyl Cyclase. Front Pharmacol. 2018;9:243. [DOI] [PubMed] [PMC]

113.

Taura J, Valle-León M, Sahlholm K, Watanabe M, Van Craenenbroeck K, Fernández-Dueñas V, et al. Behavioral control by striatal adenosine A_2A-dopamine D₂ receptor heteromers. Genes Brain Behav. 2018;17:e12432. [DOI] [PubMed]

114.

Azdad K, Gall D, Woods AS, Ledent C, Ferré S, Schiffmann SN. Dopamine D₂and adenosine A_2A receptors regulate NMDA-mediated excitation in accumbens neurons through A_2A-D₂ receptor heteromerization. Neuropsychopharmacology. 2009;34:972–86. [DOI] [PubMed] [PMC]

115.

Borroto-Escuela DO, Wydra K, Li X, Rodriguez D, Carlsson J, Jastrzębska J, et al. Disruption of A2AR-D2R Heteroreceptor Complexes After A2AR Transmembrane 5 Peptide Administration Enhances Cocaine Self-Administration in Rats. Mol Neurobiol. 2018;55:7038–48. [DOI] [PubMed] [PMC]

116.

Koob GF, Volkow ND. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry. 2016;3:760–73. [DOI] [PubMed] [PMC]

117.

Trifilieff P, Ducrocq F, van der Veldt S, Martinez D. Blunted Dopamine Transmission in Addiction: Potential Mechanisms and Implications for Behavior. Semin Nucl Med. 2017;47:64–74. [DOI] [PubMed]

118.

Cervetto C, Venturini A, Passalacqua M, Guidolin D, Genedani S, Fuxe K, et al. A2A-D2 receptor-receptor interaction modulates gliotransmitter release from striatal astrocyte processes. J Neurochem. 2017;140:268–79. [DOI] [PubMed]

119.

Cervetto C, Venturini A, Guidolin D, Maura G, Passalacqua M, Tacchetti C, et al. Homocysteine and A2A-D2 Receptor-Receptor Interaction at Striatal Astrocyte Processes. J Mol Neurosci. 2018;65:456–66. [DOI] [PubMed]

120.

Pelassa S, Guidolin D, Venturini A, Averna M, Frumento G, Campanini L, et al. A2A-D2 Heteromers on Striatal Astrocytes: Biochemical and Biophysical Evidence. Int J Mol Sci. 2019;20:2457. [DOI] [PubMed] [PMC]

121.

Cervetto C, Maura G, Guidolin D, Amato S, Ceccoli C, Agnati LF, et al. Striatal astrocytic A2A-D2 receptor-receptor interactions and their role in neuropsychiatric disorders. Neuropharmacology. 2023;237:109636. [DOI] [PubMed]

122.

Kupchik YM, Brown RM, Heinsbroek JA, Lobo MK, Schwartz DJ, Kalivas PW. Coding the direct/indirect pathways by D1 and D2 receptors is not valid for accumbens projections. Nat Neurosci. 2015;18:1230–2. [DOI] [PubMed] [PMC]

123.

Hasbi A, Sivasubramanian M, Milenkovic M, Komarek K, Madras BK, George SR. Dopamine D1-D2 receptor heteromer expression in key brain regions of rat and higher species: Upregulation in rat striatum after cocaine administration. Neurobiol Dis. 2020;143:105017. [DOI] [PubMed] [PMC]

124.

Bonnavion P, Varin C, Fakhfouri G, Martinez Olondo P, De Groote A, Cornil A, et al. Striatal projection neurons coexpressing dopamine D1 and D2 receptors modulate the motor function of D1- and D2-SPNs. Nat Neurosci. 2024;27:1783–93. [DOI] [PubMed]

125.

Deng YP, Lei WL, Reiner A. Differential perikaryal localization in rats of D1 and D2 dopamine receptors on striatal projection neuron types identified by retrograde labeling. J Chem Neuroanat. 2006;32:101–16. [DOI] [PubMed]

126.

Hasbi A, Fan T, Alijaniaram M, Nguyen T, Perreault ML, O’Dowd BF, et al. Calcium signaling cascade links dopamine D1-D2 receptor heteromer to striatal BDNF production and neuronal growth. Proc Natl Acad Sci U S A. 2009;106:21377–82. [DOI] [PubMed] [PMC]

127.

Perreault ML, Hasbi A, O’Dowd BF, George SR. Heteromeric dopamine receptor signaling complexes: emerging neurobiology and disease relevance. Neuropsychopharmacology. 2014;39:156–68. [DOI] [PubMed] [PMC]

128.

Frederick AL, Yano H, Trifilieff P, Vishwasrao HD, Biezonski D, Mészáros J, et al. Evidence against dopamine D1/D2 receptor heteromers. Mol Psychiatry. 2015;20:1373–85. [DOI] [PubMed] [PMC]

129.

Perreault ML, Hasbi A, Shen MYF, Fan T, Navarro G, Fletcher PJ, et al. Disruption of a dopamine receptor complex amplifies the actions of cocaine. Eur Neuropsychopharmacol. 2016;26:1366–77. [DOI] [PubMed]

130.

Rico AJ, Dopeso-Reyes IG, Martínez-Pinilla E, Sucunza D, Pignataro D, Roda E, et al. Neurochemical evidence supporting dopamine D1-D2 receptor heteromers in the striatum of the long-tailed macaque: changes following dopaminergic manipulation. Brain Struct Funct. 2017;222:1767–84. [DOI] [PubMed] [PMC]

131.

Hasbi A, Perreault ML, Shen MYF, Fan T, Nguyen T, Alijaniaram M, et al. Activation of Dopamine D1-D2 Receptor Complex Attenuates Cocaine Reward and Reinstatement of Cocaine-Seeking through Inhibition of DARPP-32, ERK, and ΔFosB. Front Pharmacol. 2018;8:924. [DOI] [PubMed] [PMC]

132.

Hasbi A, Perreault ML, Shen MYF, Zhang L, To R, Fan T, et al. A peptide targeting an interaction interface disrupts the dopamine D1-D2 receptor heteromer to block signaling and function in vitro and in vivo: effective selective antagonism. FASEB J. 2014;28:4806–20. [DOI] [PubMed] [PMC]

133.

O’Dowd BF, Ji X, Nguyen T, George SR. Two amino acids in each of D₁ and D₂ dopamine receptor cytoplasmic regions are involved in D₁-D₂ heteromer formation. Biochem Biophys Res Commun. 2012;417:23–8. [DOI] [PubMed] [PMC]

134.

Aguinaga D, Casanovas M, Rivas-Santisteban R, Reyes-Resina I, Navarro G, Franco R. The sigma-1 receptor as key common factor in cocaine and food-seeking behaviors. J Mol Endocrinol. 2019;63:R81–92. [DOI] [PubMed]

135.

Cai Y, Yang L, Niu F, Liao K, Buch S. Role of Sigma-1 Receptor in Cocaine Abuse and Neurodegenerative Disease. Adv Exp Med Biol. 2017;964:163–75. [DOI] [PubMed]

136.

Navarro G, Moreno E, Bonaventura J, Brugarolas M, Farré D, Aguinaga D, et al. Cocaine inhibits dopamine D₂ receptor signaling via sigma-1-D₂ receptor heteromers. PLoS One. 2013;8:e61245. [DOI] [PubMed] [PMC]

137.

Navarro G, Moreno E, Aymerich M, Marcellino D, McCormick PJ, Mallol J, et al. Direct involvement of sigma-1 receptors in the dopamine D₁ receptor-mediated effects of cocaine. Proc Natl Acad Sci U S A. 2010;107:18676–81. [DOI] [PubMed] [PMC]

138.

Casanovas M, Jiménez-Rosés M, Cordomí A, Lillo A, Vega-Quiroga I, Izquierdo J, et al. Discovery of a macromolecular complex mediating the hunger suppressive actions of cocaine: Structural and functional properties. Addict Biol. 2021;26:e13017. [DOI] [PubMed]

139.

Aguinaga D, Medrano M, Cordomí A, Jiménez-Rosés M, Angelats E, Casanovas M, et al. Cocaine Blocks Effects of Hunger Hormone, Ghrelin, Via Interaction with Neuronal Sigma-1 Receptors. Mol Neurobiol. 2019;56:1196–210. [DOI] [PubMed]

140.

Wellman M, Abizaid A. Growth Hormone Secretagogue Receptor Dimers: A New Pharmacological Target. eNeuro. 2015;2:ENEURO.0053–14.2015. [DOI] [PubMed] [PMC]

141.

Borroto-Escuela DO, Rodriguez D, Romero-Fernandez W, Kapla J, Jaiteh M, Ranganathan A, et al. Mapping the Interface of a GPCR Dimer: A Structural Model of the A_2A Adenosine and D₂ Dopamine Receptor Heteromer. Front Pharmacol. 2018;9:829. [DOI] [PubMed] [PMC]

142.

Bontempi L, Savoia P, Bono F, Fiorentini C, Missale C. Dopamine D3 and acetylcholine nicotinic receptor heteromerization in midbrain dopamine neurons: Relevance for neuroplasticity. Eur Neuropsychopharmacol. 2017;27:313–24. [DOI] [PubMed]

143.

Bono F, Mutti V, Fiorentini C, Missale C. Dopamine D3 Receptor Heteromerization: Implications for Neuroplasticity and Neuroprotection. Biomolecules. 2020;10:1016. [DOI] [PubMed] [PMC]

144.

Fiorentini C, Busi C, Spano P, Missale C. Dimerization of dopamine D1 and D3 receptors in the regulation of striatal function. Curr Opin Pharmacol. 2010;10:87–92. [DOI] [PubMed]