The Cholinergic Interneurons in the Nucleus Accumbens Mediate the Rewarding Properties of Opioid Drugs

Abstract

The majority of drugs of abuse exert their reinforcing properties through dopamine. However, opioid drugs continue to be rewarding in dopamine-depleted mice, suggesting that there is a dopamine-independent pathway underlying the reinforcing properties of opioids. The circuit mechanism of this dopamine-independent pathway remains unknown. Here, we isolated the behavioral contributions made by opioid receptors on cholinergic interneurons in the nucleus accumbens. To avoid the compensatory confounds of genetic manipulations, we used Drug Acutely Restricted by Tethering (DART) to selectively deliver the opioid receptor antagonist, naloxone, to the cholinergic interneurons in the nucleus accumbens. Drug Acutely Restricted by Tethering (DART) operates by genetically programming a designated group of cells to capture a specific drug, thereby concentrating the drug’s action on the chosen subset of cells while having minimal effects on neighboring non-target cells. Here, we developed an opioid-DART toolset and used it to examine the role of cholinergic interneurons in various behavioral assays. We find that antagonism of opioid receptors on cholinergic interneurons impedes opioid-induced positive reinforcement while having no role in opioid-induced analgesia, identifying cholinergic interneurons in the nucleus accumbens as key nodes driving the rewarding properties of opioid drugs. Our findings challenge the dopamine-centric model and suggest new strategies for addressing opioid use disorder by targeting the cholinergic pathway.