Presynaptic and Postsynaptic Mesolimbic Dopamine D 3 Receptors Play Distinct Roles in Cocaine Versus Opioid Reward in Mice

Past research has illuminated pivotal roles of dopamine D receptors (D R) in the rewarding effects of cocaine and opioids. However, the cellular and neural circuit mechanisms that underlie these actions remain unclear. We employed Cre-LoxP techniques to selectively delete D R from presynaptic dopamine neurons or postsynaptic dopamine D receptor (D R)-expressing neurons in male and female mice. We utilized RNAscope in situ hybridization, immunohistochemistry, real-time polymerase chain reaction, voltammetry, optogenetics, microdialysis, and behavioral assays (n ≥ 8 animals per group) to functionally characterize the roles of presynaptic versus postsynaptic D R in cocaine and opioid actions. Our results revealed D R expression in ∼25% of midbrain dopamine neurons and ∼70% of D R-expressing neurons in the nucleus accumbens. While dopamine D receptors (D R) were expressed in ∼80% dopamine neurons, we found no D R and D R colocalization among these cells. Selective deletion of D R from dopamine neurons increased exploratory behavior in novel environments and enhanced pulse-evoked nucleus accumbens dopamine release. Conversely, deletion of D R from D R-expressing neurons attenuated locomotor responses to D -like and D -like agonists. Strikingly, deletion of D R from either cell type reduced oxycodone self-administration and oxycodone-enhanced brain-stimulation reward. In contrast, neither of these D R deletions impacted cocaine self-administration, cocaine-enhanced brain-stimulation reward, or cocaine-induced hyperlocomotion. Furthermore, D R knockout in dopamine neurons reduced oxycodone-induced hyperactivity and analgesia, while deletion from D R-expressing neurons potentiated opioid-induced hyperactivity without affecting analgesia. We dissected presynaptic versus postsynaptic D R function in the mesolimbic dopamine system. D R and D R are expressed in different populations of midbrain dopamine neurons, regulating dopamine release. Mesolimbic D R are critically involved in the actions of opioids but not cocaine.