The Role of the Dopamine D1-D2 Receptor Heteromer in Brain Reward Function: Relevance to Drug Addiction and Depression

We have identified a novel dopamine-mediated signaling complex, the D1-D2 receptor heteromer, which couples to Gq protein to elicit phospholipase C-mediated intracellular Ca2+ release. Activation of the D1-D2 heteromer was further shown to modulate the expression of proteins implicated in reward in the nucleus accumbens, such as calcium calmodulin kinase II (CaMKII) and brain derived neurotrophic factor (BDNF), a finding which may be of relevance in neuropsychiatric disorders that exhibit altered reward perception such as addiction and depression. Therefore, the purpose of current study was to investigate a role for the D1-D2 heteromer in reward-related behaviours using animal models of cocaine addiction and depression. The results show that D1-D2 heteromer stimulation by agonist SKF 83959 attenuated addiction-related behaviours including cocaine conditioned place preference (CPP), the maintenance and reinstatement of cocaine self-administration (SA), and the expression of locomotor sensitization to cocaine, whereas D1-D2 heteromer inactivation by a selective disrupting peptide TAT-D1 consistently augmented cocaine-induced behaviours, whereas a control scrambled peptide had no such effects. Moreover, D1-D2 heteromer stimulation alone was shown to induce conditioned place aversion, whereas its selective inactivation induced CPP. In the tests for depression, D1-D2 heteromer stimulation by SKF 83959 induced a pro-depressive and anxiogenic state in the forced swim test, novelty-induced hypophagia, and the elevated plus maze, effects that were abolished by pretreatment with TAT-D1 peptide. Lastly, it was shown that the D1-D2 heteromer exerts dual modulation on neuronal activity in certain regions of brain, increasing activity in the NAc, and exerting tonic inhibition in the prelimbic and infralimbic cortex, orbitofrontal cortex, lateral habenula, and the thalamus, which likely reflects the dual excitatory/inhibitory capabilities of the GABA/Glu-co-expressing D1R/D2R MSNs. Collectively, these findings indicate that the D1-D2 heteromer may be a single molecular entity that could bidirectionally modulate brain reward function depending on its state of activation. Such an unprecedented function of a receptor complex makes the D1-D2 heteromer an attractive and novel therapeutic target for cocaine addiction and major depression, two reward-related neuropsychiatric disorders that are currently without effective treatments.Ph.D.2018-02-19 00:00:0