A cholinergic hub in the nucleus accumbens gates opioid-reward learning
Beneficial and maladaptive opioid effects are difficult to dissociate, partly because dopamine signaling contributes to both. Here we show that associative opioid-reward learning can be blocked even under conditions that elevate dopamine in the nucleus accumbens. We developed naloxoneDART, a cell-type-specific analogue of the clinical opioid-receptor antagonist, and delivered it to genetically defined accumbal cholinergic interneurons (CINs), selectively rendering these cells morphine-insensitive. Acquisition of morphine conditioned place preference was abolished in a target-engagement-dependent manner, without evidence of contextual or locomotor impairment: saline habituation was enhanced between sessions and unchanged within sessions, while morphine-evoked hyperlocomotion, sensitization, and acute analgesia remained intact. Microdialysis revealed that CIN-specific naloxoneDART prevented morphine-induced acetylcholine reductions without detectably altering dopamine elevations in the accumbens. These findings identify a cholinergic gate for associative opioid-reward learning, support an emerging dopamine-acetylcholine plasticity theory, and motivate exploration of opioid-cholinergic strategies that may preserve acute analgesia while limiting early associative reward learning.