TY - JOUR T1 - Mu opioid receptors on distinct neuronal populations mediate different aspects of opioid reward-related behaviors JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0146-20.2020 SP - ENEURO.0146-20.2020 AU - Amie L. Severino AU - Nitish Mittal AU - Joshua K. Hakimian AU - Nathanial Velarde AU - Ani Minasyan AU - Ralph Albert AU - Carlos Torres AU - Nicole Romaneschi AU - Camille Johnston AU - Suchi Tiwari AU - Alex S. Lee AU - Anna M. Taylor AU - Claire Gavériaux-Ruff AU - Brigitte L Kieffer AU - Christopher J. Evans AU - Catherine M. Cahill AU - Wendy M. Walwyn Y1 - 2020/08/28 UR - http://www.eneuro.org/content/early/2020/08/28/ENEURO.0146-20.2020.abstract N2 - Mu opioid receptors (MORs) are densely expressed in different brain regions known to mediate reward. One such region is the striatum where MORs are densely expressed, yet the role of these MOR populations in modulating reward is relatively unknown. We have begun to address this question by using a series of genetically engineered mice based on the Cre recombinase/loxP system to selectively delete MORs from specific neurons enriched in the striatum; dopamine 1 receptors (D1), dopamine 2 receptors (D2), adenosine 2a receptors (A2a) and Choline Acetyl Transferase (ChAT). We first determined the effects of each deletion on opioid-induced locomotion, a striatal and dopamine dependent behavior. We show that MOR deletion from D1 neurons reduced opioid (morphine and oxycodone)-induced hyperlocomotion whereas deleting MORs from A2a neurons resulted in enhanced opioid-induced locomotion, and deleting MORs from D2 or ChAT neurons had no effect. We also present the effect of each deletion on opioid intravenous self-administration. We first assessed the acquisition of this behavior using remifentanil as the reinforcing opioid and found no effect of genotype. Mice were then transitioned to oxycodone as the reinforcer and maintained here for 9 days. Again no genotype effect was found. However, when mice underwent 3 days of extinction training, during which the drug was not delivered but all cues remained as during the maintenance phase, drug-seeking behavior was enhanced when MORs were deleted from A2a or ChAT neurons. These findings show that these selective MOR populations play specific roles in reward-associated behaviors.Significance Statement Mu opioid receptors mediate the effects of the commonly misused and prescribed opioids. These receptors are expressed in different neurons and pathways mediating reward. Although it is well-known that mu receptors in the midbrain regulate dopamine release and are important in mediating reward, little is known of the role of other populations that are expressed in the different neurons of the striatum, a hub of many reward pathways. In this study we deleted selective populations of these receptors that are enriched in the striatum and studied the effect of each deletion on reward-related behaviors. We found that each population plays a specific role in reward demonstrating a more complex role than previously thought of how these receptors mediate reward. ER -