Open AccessBiased G Protein-Independent Signaling of Dopamine D1-D3 Receptor Heteromers in the Nucleus Accumbens
Author(s) -
Xavier Guitart,
Estefanía Moreno,
William Rea,
Marta Sánchez-Soto,
Ning-Sheng Cai,
César Quiroz,
Vivek Kumar,
Liam Bourque,
Antoni Cortés,
Enric I. Canela,
Christopher Bishop,
Amy Hauck Newman,
Vicent Casadó,
Sergi Ferré
Publication year - 2019
Publication title -
molecular neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.569
H-Index - 111
eISSN - 1559-1182
pISSN - 0893-7648
DOI - 10.1007/s12035-019-1564-8
Subject(s) - nucleus accumbens , striatum , dopamine , chemistry , dopamine receptor , medium spiny neuron , dopamine receptor d3 , microbiology and biotechnology , receptor , neuroscience , biology , biochemistry
Several studies found in vitro evidence for heteromerization of dopamine D 1 receptors (D1R) and D 3 receptors (D3R), and it has been postulated that functional D1R-D3R heteromers that are normally present in the ventral striatum mediate synergistic locomotor-activating effects of D1R and D3R agonists in rodents. Based also on results obtained in vitro, with mammalian transfected cells, it has been hypothesized that those behavioral effects depend on a D1R-D3R heteromer-mediated G protein-independent signaling. Here, we demonstrate the presence on D1R-D3R heteromers in the mouse ventral striatum by using a synthetic peptide that selectively destabilizes D1R-D3R heteromers. Parallel locomotor activity and ex vivo experiments in reserpinized mice and in vitro experiments in D1R-D3R mammalian transfected cells were performed to dissect the signaling mechanisms of D1R-D3R heteromers. Co-administration of D1R and D3R agonists in reserpinized mice produced synergistic locomotor activation and a selective synergistic AKT phosphorylation in the most ventromedial region of the striatum in the shell of the nucleus accumbens. Application of the destabilizing peptide in transfected cells and in the shell of the nucleus accumbens allowed demonstrating that both in vitro and in vivo co-activation of D3R induces a switch from G protein-dependent to G protein-independent D1R-mediated signaling determined by D1R-D3R heteromerization. The results therefore demonstrate that a biased G protein-independent signaling of D1R-D3R heteromers localized in the shell of the nucleus accumbens mediate the locomotor synergistic effects of D1R and D3R agonists in reserpinized mice.