Abstract
Parkinson’s disease is a progressive motor disorder characterised by dopaminergic neuron degeneration. Existing dopaminomimetic therapies are limited by side effects and diminishing efficacy with chronic use and off-target actions, highlighting the need for more precise treatments. One promising strategy utilises transcranial focused ultrasound (US) to locally release the dopamine D2 receptor agonist ropinirole from circulating US-sensitive liposomes (“ropinisomes”) within the striatum. This approach provides spatiotemporally precise neuromodulation, aiming to limit systemic exposure and associated adverse effects to enhance clinical efficacy.
Foundational studies in the Reynolds lab have previously characterised the striatal effects of this system in anaesthetised rats, using fibre photometry (FP) to measure calcium activity via the genetically encoded calcium indicator GCaMP6s. The aim of the current study was to extend these findings to awake, freely moving animals with three objectives: (1) characterise striatal-neural responses to subcutaneous ropinirole injection; (2) develop an integrated US/FP stimulation/recording system; and (3) evaluate US-triggered ropinisome release.
For Objective 1, subcutaneous ropinirole (1mg/kg, n = 5) significantly suppressed striatal calcium transients (>40%) across three 5-minute post-injection epochs (repeated measures ANOVA, F(9,40) = 34.2, P < 0.0001; Dunnett’s: P < 0.01 for each epoch). Prior to antagonist administration, activity spontaneously rebounded above baseline (P = 0.031), implying a compensatory mechanism (e.g., D2 receptor internalisation) absent in anaesthetised states.
While Objective 2 was achieved (n = 6), technological complications reduced the usable sample size (n = 2), rendering Objective 3 inconclusive. Qualitatively, no US-triggered neural suppression was observed; however, US application alone appeared to modestly increase neural activity.
In conclusion, subcutaneous ropinirole induced a marked suppression followed by spontaneous rebound hyperactivity in the awake rat striatum. A novel, US/FP implant paradigm was established to permit simultaneous stimulation/recording; however, US-mediated drug delivery was inconclusive due to low sample size. This work will inform the development of a targeted US-based drug delivery strategy for Parkinson’s disease.