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

@article{pmid38838841,

title = {Presynaptic and Postsynaptic Mesolimbic Dopamine D_{3} Receptors Play Distinct Roles in Cocaine Versus Opioid Reward in Mice},

author = {Zheng-Xiong Xi and Miriam E Bocarsly and Ewa Galaj and Briana Hempel and Catherine Teresi and Marlisa Shaw and Guo-Hua Bi and Chloe Jordan and Emily Linz and Hannah Alton and Gianluigi Tanda and Zachary Freyberg and Veronica A Alvarez and Amy Hauck Newman},

url = {https://pubmed.ncbi.nlm.nih.gov/38838841/},

doi = {10.1016/j.biopsych.2024.05.020},

issn = {1873-2402},

year  = {2024},

date = {2024-06-01},

urldate = {2024-06-01},

journal = {Biol Psychiatry},

abstract = {Background: Past research has illuminated pivotal roles of dopamine D3 receptors (D_{3}R) 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 D_{3}R from presynaptic dopamine neurons or postsynaptic dopamine D_{1} receptor (D_{1}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_{3}R in cocaine and opioid actions.



Results: Our results revealed D_{3}R expression in ∼25% of midbrain dopamine neurons and ∼70% of D_{1}R-expressing neurons in the nucleus accumbens. While dopamine D_{2} receptors (D_{2}R) were expressed in ∼80% dopamine neurons, we found no D_{2}R and D_{3}R colocalization among these cells. Selective deletion of D_{3}R from dopamine neurons increased exploratory behavior in novel environments and enhanced pulse-evoked nucleus accumbens dopamine release. Conversely, deletion of D_{3}R from D_{1}R-expressing neurons attenuated locomotor responses to D_{1}-like and D_{2}-like agonists. Strikingly, deletion of D_{3}R from either cell type reduced oxycodone self-administration and oxycodone-enhanced brain-stimulation reward. In contrast, neither of these D_{3}R deletions impacted cocaine self-administration, cocaine-enhanced brain-stimulation reward, or cocaine-induced hyperlocomotion. Furthermore, D_{3}R knockout in dopamine neurons reduced oxycodone-induced hyperactivity and analgesia, while deletion from D_{1}R-expressing neurons potentiated opioid-induced hyperactivity without affecting analgesia.



Conclusions: We dissected presynaptic versus postsynaptic D_{3}R function in the mesolimbic dopamine system. D_{2}R and D_{3}R are expressed in different populations of midbrain dopamine neurons, regulating dopamine release. Mesolimbic D_{3}R are critically involved in the actions of opioids but not cocaine.



Keywords: Cocaine; Conditional D(3) receptor knockout; Dopamine D(3) receptor; Opioid; Optical brain stimulation reward; Self-administration.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}