UC San Diego

Opioid drugs, such as morphine, bind to opioid receptors in the brain and provide an analgesic, rewarding, and euphoric effect. Endogenous opioid peptides also bind to opioid receptors in response to natural rewards such as food and exercise. The hijacking of these natural reward circuits have been hypothesized to lead to addiction. Basal ganglia nuclei are rich in opioid neuropeptides and these opioid neuropeptides and their receptors have been implicated in supporting behavior reinforcement for rewards. The striatum, a major basal ganglia input nuclei, is a mu opioid receptor hotspot. The striatum is implicated in goal directed, habitual and decision-making behaviors, as well as drug addiction, but the role of striatal opioid signaling in the learning and successful completion of operant behaviors and drug reward have yet to be established. To understand how opioid neuropeptides within striatal microcircuits contribute to operant behaviors and opioid drug we used two main approaches. We genetically deleted mu opioid receptors (MORs) from striatal direct pathway neurons, or selectively removed MORs from different striatal regions using AAV-cre. In both cases we found that lever pressing for food rewards was unaffected. In parallel, to test the role of striatal MORs in opioid drug reward, using the same genetic and viral manipulations we ran mice through a morphine conditioned place preference (CPP) assay and found that these animals established a place preference for the morphine-paired chamber. These results indicate that MORs in striatal direct pathway neurons may not be involved in operant behaviors or opioid drug reward.