G protein-coupled receptors are known to form homo- and heteromers at the plasma membrane, but the stoichiometry of these receptor oligomers are relatively unknown. Here, by using bimolecular fluorescence complementation, we visualized for the first time the occurrence of heterodimers of metabotropic glutamate mGlu5 receptors (mGlu5R) and dopamine D2 receptors (D2R) in living cells. Furthermore, the combination of bimolecular fluorescence complementation and bioluminescence resonance energy transfer techniques, as well as the sequential resonance energy transfer (SRET) technique, allowed us to detect the occurrence receptor oligomers containing more than two protomers, mGlu5R, D2R and adenosine A2A receptor (A2AR). Interestingly, by using high-resolution immunoelectron microscopy we could confirm that the three receptors co-distribute within the extrasynaptic plasma membrane of the same dendritic spines of asymmetrical, putative glutamatergic, striatal synapses. Also, co-immunoprecipitation experiments in native tissue demonstrated the existence of an association of mGlu5R, D2R and A2AR in rat striatum homogenates. Overall, these results provide new insights into the molecular composition of G protein-coupled receptor oligomers in general and the mGlu5R/D2R/A2AR oligomer in particular, a receptor oligomer that might constitute an important target for the treatment of some neuropsychiatric disorders.

The endogenous opioid system is well known to relieve pain and underpin the rewarding properties of most drugs of abuse. Among opioid receptors, the μ receptor mediates most of the analgesic and rewarding properties of opioids. Based on striking similarities between social distress, physical pain and opiate withdrawal, μ receptors have been proposed to play a critical role in modulating social behaviour in humans and animals. This review summarizes experimental data demonstrating such role and proposes a novel model, the μ opioid receptor balance model, to account for the contribution of μ receptors to the subtle regulation of social behaviour. Interestingly, μ receptor null mice show behavioural deficits similar to those observed in patients with autism spectrum disorder (ASD), including severe impairment in social interactions. Therefore, after a brief summary of recent evidence for blunted (social) reward processes in subjects with ASD, we review here arguments for altered μ receptor function in this pathology. This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.