Presynaptic and Postsynaptic Mesolimbic Dopamine D₃ Receptors Play Distinct Roles in Cocaine Versus Opioid Reward in...

Past research has illuminated pivotal roles of dopamine D₃ receptors (D₃R) 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 D₃R from presynaptic dopamine neurons or postsynaptic dopamine D₁ receptor (D₁R)-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 D₃R in cocaine and opioid actions.

Our results revealed D₃R expression in ∼25% of midbrain dopamine neurons and ∼70% of D₁R-expressing neurons in the nucleus accumbens. While dopamine D₂ receptors (D₂R) were expressed in ∼80% dopamine neurons, we found no D₂R and D₃R colocalization among these cells. Selective deletion of D₃R from dopamine neurons increased exploratory behavior in novel environments and enhanced pulse-evoked nucleus accumbens dopamine release. Conversely, deletion of D₃R from D₁R-expressing neurons attenuated locomotor responses to D₁-like and D₂-like agonists. Strikingly, deletion of D₃R from either cell type reduced oxycodone self-administration and oxycodone-enhanced brain-stimulation reward. In contrast, neither of these D₃R deletions impacted cocaine self-administration, cocaine-enhanced brain-stimulation reward, or cocaine-induced hyperlocomotion. Furthermore, D₃R knockout in dopamine neurons reduced oxycodone-induced hyperactivity and analgesia, while deletion from D₁R-expressing neurons potentiated opioid-induced hyperactivity without affecting analgesia.

We dissected presynaptic versus postsynaptic D₃R function in the mesolimbic dopamine system. D₂R and D₃R are expressed in different populations of midbrain dopamine neurons, regulating dopamine release. Mesolimbic D₃R are critically involved in the actions of opioids but not cocaine.