Beneficial and maladaptive opioid effects are difficult to dissociate1–3, partly because dopamine signalling contributes to both these effect types4–13. 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 naloxone14,15, and delivered it to genetically defined accumbal cholinergic interneurons, 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, whereas morphine-evoked hyperlocomotion, sensitization and acute analgesia remained intact. Microdialysis revealed that cholinergic interneuron-specific naloxoneDART prevented morphine-induced acetylcholine reductions without detectably altering dopamine increases in the accumbens. These findings identify a cholinergic gate for associative opioid-reward learning, support an emerging dopamine–acetylcholine plasticity theory16,17, and motivate exploration of opioid–cholinergic strategies that may preserve acute analgesia while limiting early associative reward learning18–25.
