Reeves, Kaitlin C.Kube, Megan J.Grecco, Gregory G.Fritz, Brandon M.Muñoz, BraulioYin, FuqinGao, YongHaggerty, David L.Hoffman, Hunter J.Atwood, Brady K.2023-01-312023-01-312021-05Reeves KC, Kube MJ, Grecco GG, et al. Mu opioid receptors on vGluT2-expressing glutamatergic neurons modulate opioid reward. Addict Biol. 2021;26(3):e12942. doi:10.1111/adb.12942https://hdl.handle.net/1805/31063The role of Mu opioid receptor (MOR)-mediated regulation of GABA transmission in opioid reward is well established. Much less is known about MOR-mediated regulation of glutamate transmission in the brain and how this relates to drug reward. We previously found that MORs inhibit glutamate transmission at synapses that express the Type 2 vesicular glutamate transporter (vGluT2). We created a transgenic mouse that lacks MORs in vGluT2-expressing neurons (MORflox-vGluT2cre) to demonstrate that MORs on the vGluT2 neurons themselves mediate this synaptic inhibition. We then explored the role of MORs in vGluT2-expressing neurons in opioid-related behaviors. In tests of conditioned place preference, MORflox-vGluT2cre mice did not acquire place preference for a low dose of the opioid, oxycodone, but displayed conditioned place aversion at a higher dose, whereas control mice displayed preference for both doses. In an oral consumption assessment, these mice consumed less oxycodone and had reduced preference for oxycodone compared with controls. MORflox-vGluT2cre mice also failed to show oxycodone-induced locomotor stimulation. These mice displayed baseline withdrawal-like responses following the development of oxycodone dependence that were not seen in littermate controls. In addition, withdrawal-like responses in these mice did not increase following treatment with the opioid antagonist, naloxone. However, other MOR-mediated behaviors were unaffected, including oxycodone-induced analgesia. These data reveal that MOR-mediated regulation of glutamate transmission is a critical component of opioid reward.en-USAttribution 4.0 InternationalElectrophysiologyGlutamateMu opioid receptorRewardTransgenic micevGluT2Article