title: Disruption of a dopamine receptor complex amplifies the actions of cocaine.
abstract: Cocaine-induced increases in dopamine signaling in nucleus accumbens (NAc) play a significant role in cocaine seeking behavior. The majority of cocaine addiction research has focused on neuroanatomically segregated dopamine D1 and D2 receptor-expressing neurons, yet an involvement for those NAc neurons coexpressing D1 and D2 receptors in cocaine addiction has never been explored. In situ proximity ligation assay, confocal fluorescence resonance energy transfer and coimmunoprecipitation were used to show native D1 and D2 receptors formed a heteromeric complex in D1/D2 receptor-coexpressing neurons in rat and non-human primate NAc. D1-D2 heteromer expression was lower in NAc of adolescent rats compared to their adult counterparts. Functional disruption of the dopamine D1-D2 receptor heteromer, using a peptide targeting the site of interaction between the D1 and D2 receptor, induced conditioned place preference and increased NAc expression of ∆FosB. D1-D2 heteromer disruption also resulted in the promotion, exacerbation and acceleration of the locomotor activating and incentive motivational effects of cocaine in the self-administration paradigm. These findings support a model for tonic inhibition of basal and cocaine-induced reward processes by the D1-D2 heteromer thus highlighting its potential value as a novel target for drug discovery in cocaine addiction. Given that adolescents show increased drug abuse susceptibility, an involvement for reduced D1-D2 heteromer function in the heightened sensitivity to the rewarding effects of cocaine in adolescence is also implicated.
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Perreault
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Hasbi
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: Maurice Y F
authors.initials: MYF
authors.lastname: Shen
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: Theresa
authors.initials: T
authors.lastname: Fan
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Navarro
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Departments of Psychology and Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fletcher
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain; CIBERNED, Centro de Investigación en Red. Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Franco
authors.affiliation: CIBERNED, Centro de Investigación en Red. Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain; Department of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Lanciego
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada. Electronic address: s.george@utoronto.ca.
authors.forename: Susan R
authors.initials: SR
authors.lastname: George
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D009042:Motivation / Q000187:drug effects / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012646:Self Administration; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology
chemical_list: D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; C483820:Fosb protein, rat; D016760:Proto-Oncogene Proteins c-fos; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D003042:Cocaine
keywords: Calcium; Cocaine; Confocal FRET; Dopamine D1–D2 heteromer; Nucleus accumbens; Proximity ligation assay; Self-administration; ∆FosB