Several DA receptors heteromers with a therapeutic potential
Several DA receptors heteromers with a therapeutic potential have been described, including D1R/D3R (Fiorentini et al., 2010), but their roles remain to be established. Moreover, most studies on receptor heteromers in addiction focused on the striatum because of its key role in the pathology and its enrichment in DA receptors. However, a thorough characterization of heteromer expression within the entire CGP 57380 reward circuit would be of importance considering the implication of various brain regions in distinct components of addiction. Moreover, the implication of DA receptor heteromers has been mainly studied in the initial phases of drug exposure. Addressing their roles in each phases of drug addiction (maintenance, craving and relapse) seems of crucial importance as it could open new routes for the development of selective strategies targeting these heteromers for the treatment of drug addiction.
Declaration of interest
Acknowledgements The work from PV's group was supported by Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université, Agence Nationale pour la Recherche (ANR-15-CE16-0017), Fondation Jérôme Lejeune, Fondation pour la Recherche Médicale (FRM), the Bio-Psy labex cluster of excellence and the Ecole des Neurosciences de Paris (ENP). AA is the recipient of PhD fellowship from the French ministry of research. PT was supported by Institut National de la Recherche Agronomique (INRA, University of Bordeaux, Région Aquitaine, ANR “SynLip” (ANR-16-CE16-0022), Idex Bordeaux “chaire d'installation” (ANR-10-IDEX-03-02) and NARSAD Young Investigator Grant from the Brain and Behavior Foundation. RW is the recipient of PhD fellowship from the French ministry of research.
Introduction Substance abuse is a chronic relapsing disorder, characterized by compulsive drug use despite harmful consequences . Brain’s reward system is the common characteristic of all kinds of drug of abuse . The mesocortical dopamine system is a fundamental component of the reward system, which plays an essential role in drug abuse . It has been shown that drugs of abuse cause the release of dopamine and opioid peptides into the ventral striatum [31,47]. This causes “high” sensation in abusers , which is related to the fast and steep enhancement of dopamine activation in dopamine receptor (DR) type 1. In contrast, stimulation of DR type 2 inhibits reward system [6,34]. D1-like DRs are expressed especially in the mesolimbic and mesocortical areas  and coupled with Gα-s which activates adenylyl cyclase (AC) . D1-like DRs consist of two receptors: (1) DRD1 and (2) DRD5 and both of them have common pharmacological features. D2-like DRs have three members: (1) DRD2, (2) DRD3 and (3) DRD4. D2-like DRs contract with Gi and inhibit AC activity . Conditioning-induced by drugs needs the stimulation of D1-like DRs . D1-like DRs have low affinity for dopamine in comparison with D2-like. Thus, D1-like DRs are activated when exposed to an enormous amount of dopamine which occurs in intoxication phase . There are studies indicating that an imbalance between DRD1 and DRD2 signaling causes compulsive drug abuse [4,21]. In the ventral tegmental area (VTA), dopaminergic neurons innervate the nucleus accumbens (NAC). Also, morphine inhibits GABAergic interneurons located in the VTA, which leads to activation of dopamine projecting neurons and increase in dopamine in the NAC. In addition, morphine acts on opioid receptors located in the NAC neurons .The NAC is involved in drug-seeking behavior . The role of NAC is translation of motivational inputs from the limbic system into the goal-directed behavior and self-control (prefrontal cortex (PFC) has a role in this action) . Amygdala complex is involved in attributing emotional value to cues  and plays a critical role in drug and cue-induced craving . In addition, amygdala is involved in mood regulation and stress reactivity during withdrawal . Pervious study revealed that in opiate and alcohol abusers, the volume of the amygdala significantly reduced. This reduction in the amygdala volume is associated with abnormalities in the cognitive memory task and decision making [25,53].