MR-Guided Focused Ultrasound Neuromodulation of Nucleus Accumbens to Attenuate Oral Fentanyl Motivation in A Self-Administration Rat Model

Introduction: Transcranial low-intensity focused ultrasound (LIFU) is being explored as a non-invasive approach for neuromodulation to treat opioid use disorder (OUD). Methods: We evaluated MR-guided focused ultrasound, with LIFU, targeting nucleus accumbens (MRgLIFU-NAc) bilaterally, using MR-acoustic radiation force-imaging (MR-ARFI) to ensure accurate targeting and adjust for FUS intensity delivered at the target. Male and female rats were trained to self-administer fentanyl/sucrose (70ug/ml fentanyl citrate in 5% sucrose) or 5% sucrose alone. Three cohorts of rats (total n=76) were evaluated on progressive ratio (PR) responding for oral fentanyl/sucrose at either 4 or 24 hours post-MRgLIFU-NAc. Animals in the first two cohorts received repeated rounds of LIFU or sham (anesthesia-duration matched). In cohort 3, we used a counterbalanced within-subjects design in which rats received both LIFU and sham one week apart. Results: Reducing sucrose concentrations decreased responding for sucrose alone more than for fentanyl/sucrose, demonstrating a role for fentanyl in the reinforcing properties of fentanyl/sucrose. Across three sonication schemes, MRgLIFU-NAc did not attenuate PR performance for oral fentanyl/sucrose at 4 or 24-hours post-LIFU relative to controls. Adjusting LIFU intensity with MR-ARFI did not correlate with changes in PR from baseline. We confirmed that NAc is the correct target by bilateral inactivation of NAc with muscimol/baclofen mixture (50 + 50 ng/side), which reduced PR responding for fentanyl/sucrose. Conclusion: The three sets of LIFU parameters, with repeated MRgLIFU-NAc sessions, did not produce detectable changes in oral fentanyl/sucrose motivation. Further studies are required to determine effective LIFU parameters needed to reduce NAc-dependent fentanyl motivation.