Modulation and functions of dopamine receptor heteromers in drugs of abuse-induced adaptations

Drug addiction is a chronic and relapsing disorder that leads to compulsive drug intake despite deleterious consequences. By increasing dopamine (DA) in the mesolimbic system, drugs of abuse hijack the brain reward circuitry, which is critical for the development of enduring behavioral alterations. DA mainly acts onto DA D1 (D1R) and D2 (D2R) receptor subtypes, which are positively and negatively coupled to adenylyl cyclase, respectively. Extensive research has aimed at targeting these receptors for the treatment of addiction, however this often results in unwanted side-effects due to the implication of DA receptors in numerous physiological functions. A growing body of evidence indicates that the physical interaction of DA receptors with other receptors can finely tune their function, making DA receptor heteromers promising targets for more specific treatment strategies. An increasing number of articles highlighted the ability of both D1R and D2R to form heteromers, however, most studies carried out to date stem from observations in heterologous systems and the biological significance of DA receptor heteromers in vivo is only emerging. We focused this review on studies that were able to provide insights into functions on D1R and D2R heteromers in drug-evoked adaptations and discuss the limitations of current approaches to study receptor heteromers in vivo. This article is part of the Special Issue entitled ‘Receptor heteromers and their allosteric receptor-receptor interactions’. •Many DAR heteromers have been identified but their biological significance is only emerging.•Targeting DAR heteromers has a strong therapeutic potential the field of addiction.•The selective inhibition of receptor heteromers is a major limitation to uncover their roles in vivo.