Date of Award

6-2-2026

Embargo Period

6-16-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Thomas Jhou

Second Advisor

Makoto Taniguchi

Third Advisor

Joseph Cheer

Fourth Advisor

Barbara Juarez

Fifth Advisor

Ewoud Schmidt

Sixth Advisor

Takashi Sato

Abstract

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, and disrupt conditioned responding to aversive stimuli, 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 during naturalistic reward and aversive processing. Because MOR effects on CS-evoked phasic DA are largely unexamined, we conducted in vivo fiber photometric recordings in water-deprived male and female mice during a classical conditioning paradigm to examine acute fentanyl’s effects on CS-evoked DA and conditioned responses to three distinct auditory tones predicting either a liquid sucrose unconditioned stimulus (US), non-reward, or an electric footshock US. 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, whereas 0.2 mg/kg fentanyl reduced anticipatory behavioral inhibitions during the presentation of the aversive CS. In parallel with these behavioral changes, acute fentanyl at either dose increased tonic DA while reducing phasic DA excitations to the reward CS. Both doses of fentanyl also decreased excitatory DA release patterns and attenuated inhibitory DA responses in the VS during the presentation of the aversive CS. In contrast to fentanyl’s effects, during water-sated states we observed decreased DA responses to both the reward CS and US, suggesting 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. In summary, we identified a novel phenomenon by which the highly selective MOR agonist fentanyl modulates phasic DA responses to reward and aversive predictive cues while also reducing cued reward-seeking and conditioned responding to aversive stimuli. The observed reduction in excitatory responses to the reward and aversive CS are in the opposite direction of the long-recognized effects of opioids on tonic DA. Hence, opioid-induced alterations in DA function are likely more complex than commonly recognized, and with distinct actions on distinct circuits governing conditioned responding to environmental cues.

Rights

Copyright is held by the author. All rights reserved.

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