Elvig, S. K. | Search bioRxiv

bioRxiv2026

Neurobehavioral effects of focused ultrasound-mediated blood-brain barrier opening

Microbubble-enhanced focused ultrasound (MB-FUS) enables noninvasive blood-brain barrier (BBB) opening to improve the delivery of drugs and other therapeutics to the brain, supporting more effective treatment of brain disorders. The benefits of this rapidly advancing and highly versatile technology have been demonstrated in clinical trials, sparking a growing interest in expanding FUS applications that require higher intensity treatments, larger targeted brain volumes and larger therapeutics. However, in-depth safety profiling of such treatments has not been done and is limited in the clinic. Preclinical studies have been restricted in their readouts, focusing on acute imaging and simple behaviors. To address the need for more holistic safety profiling, we present a novel preclinical workflow for determining adverse effects of MB-FUS in rats, both acutely and long-term, by combining MRI, histology, and a custom motor task which provides fine-scaled readouts for complex learned behavior. Using this approach and taking advantage of our previous delineation of the relevant circuitry, we show dose- and target-dependent adverse effects in high dosing regimens. All prescribed acoustic doses opened the BBB; but while low doses had no overt adverse effects, high doses targeting the involved circuitry had severe effects on both behavior and brain tissue integrity. These effects persisted for weeks and recovered over differing time courses, with tissue disruptions and behavioral changes outlasting general performance deficits. Our results reinforce the need for multimodal, highly sensitive, and longitudinal readouts to holistically characterize adverse effects of MB-FUS, allowing for its safe use across a wide range of applications. SignificanceMicrobubble-enhanced focused ultrasound is emerging as a powerful noninvasive approach for delivering drugs, genes, and cell therapies through the blood-brain barrier, sparking broad interest in expanding clinical and preclinical applications. However, its effects on complex neurological function, especially for higher dosing regimens, remain poorly defined. To address this, we have established a novel multimodal preclinical strategy for defining functional safety limits and guiding clinical translation, integrating sensitive behavioral testing with MRI, histology and acoustic emissions analysis. We show dose- and target-dependent impairments in complex learned motor behavior and evidence of possible brain injury, with substantially different recovery time courses. Together, our findings demonstrate the importance of a multimodal, longitudinal approach for comprehensively characterizing treatment-related adverse effects and evaluating safety.

neuroscience↗

bioRxiv2019

Oral prescription opioid-seeking behavior in male and female mice

A significant portion of prescription opioid users self-administer orally rather than intravenously. Animal models of opioid addiction have demonstrated that intravenous cues are sufficient to cause drug-seeking. However, intravenous models may not model oral users, and the preference to self-administer orally appears to be partially influenced by the users sex. Our objectives were to determine whether oral opioid-associated cues are sufficient for relapse and whether sex differences exist in relapse susceptibility. Mice orally self-administered escalating doses of oxycodone under postprandial (prefed) or non-postprandial (no prefeeding) conditions. Both sexes demonstrated robust cue-induced reinstatement. In separate mice we found that oral oxycodone cues were sufficient to reinstate extinguished oral oxycodone-seeking behavior in the absence of postprandial or prior water self-administration training. During self-administration, we found that female mice earned significantly more mg/kg oxycodone than male mice. Follow-up studies indicated sex differences in psychomotor stimulation and plasma oxycodone/oxymorphone following oral oxycodone administration. In addition, gonadal steroid studies were performed in which we found divergent responses where ovariectomy enhanced and orchiectomy suppressed oral self-administration. While the suppressive effects of orchiectomy were identified across doses and postprandial conditions, the enhancing effects of ovariectomy were selective to non-postprandial conditions. These studies establish that 1) oral drug cues are sufficient to cause reinstatement that is independent of prandial conditions and water-seeking behavior, 2) earned oral oxycodone is larger in female mice compared with male mice potentially through differences in psychomotor stimulation and drug metabolism, and 3) gonadectomy produces divergent effects on oral oxycodone self-administration between sexes.

neuroscience↗