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<p>Mu opioid receptor (MOR) agonists are recognized to disinhibit tonic dopamine (DA) in the ventral striatum (VS), contributing to opioid addiction and euphoria. However, MOR agonists can also inhibit non-drug reward-seeking, a phenomenon not readily explained by tonic DA disinhibition. We hypothesized that this effect could be due in part to disruption of phasic DA responses to conditioned stimuli (CS) which critically shape and maintain behaviors to obtain rewards. Because MOR effects on CS-evoked phasic DA are largely unexamined, we used fiber photometry in water-deprived male and female mice to examine acute fentanyl’s effects on CS-evoked DA responses to two distinct auditory CS predicting either a liquid sucrose unconditioned stimulus (US), or non-reward. Behaviorally, we observed that acute fentanyl (0.1 or 0.2 mg/kg subcutaneous) increased generalized locomotion while dose-dependently reducing CS-driven anticipatory nose poke entries into the reward port during water deprived states. In parallel with these behavioral changes, acute fentanyl at either dose increased tonic DA while reducing phasic DA responses to the reward CS. In contrast to fentanyl’s effects, during water-sated states we observed decreased DA responses to both the reward CS and US. Overall, our findings suggest that MOR agonists reduce cue-driven motivational behavior for non-drug rewards, and influence tonic and reward cue-evoked DA in opposite directions, but in a manner different from the effects of satiation.</p>

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Acute fentanyl induces opposing directions of changes in tonic and phasic dopamine release patterns and impairs Pavlovian task performance

  • 期刊论文

  • 发表日期：

    2026年5月14日

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  • Oliver P. Culver,
  • Ren E. Thigpen,
  • Thomas C. Jhou

摘要

Mu opioid receptor (MOR) agonists are recognized to disinhibit tonic dopamine (DA) in the ventral striatum (VS), contributing to opioid addiction and euphoria. However, MOR agonists can also inhibit non-drug reward-seeking, a phenomenon not readily explained by tonic DA disinhibition. We hypothesized that this effect could be due in part to disruption of phasic DA responses to conditioned stimuli (CS) which critically shape and maintain behaviors to obtain rewards. Because MOR effects on CS-evoked phasic DA are largely unexamined, we used fiber photometry in water-deprived male and female mice to examine acute fentanyl’s effects on CS-evoked DA responses to two distinct auditory CS predicting either a liquid sucrose unconditioned stimulus (US), or non-reward. Behaviorally, we observed that acute fentanyl (0.1 or 0.2 mg/kg subcutaneous) increased generalized locomotion while dose-dependently reducing CS-driven anticipatory nose poke entries into the reward port during water deprived states. In parallel with these behavioral changes, acute fentanyl at either dose increased tonic DA while reducing phasic DA responses to the reward CS. In contrast to fentanyl’s effects, during water-sated states we observed decreased DA responses to both the reward CS and US. Overall, our findings suggest that MOR agonists reduce cue-driven motivational behavior for non-drug rewards, and influence tonic and reward cue-evoked DA in opposite directions, but in a manner different from the effects of satiation.