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

BACKGROUND

Past research has illuminated pivotal roles of dopamine D receptors (DR) in the rewarding effects of cocaine and opioids. However, the cellular and neural circuit mechanisms that underlie these actions remain unclear.

METHODS

We employed Cre-LoxP techniques to selectively delete DR from presynaptic dopamine neurons or postsynaptic dopamine D receptor (DR)-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 DR in cocaine and opioid actions.

RESULTS

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

CONCLUSIONS

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