Objective: To emulate physiological dopamine receptor activation, in order to restore temporal patterns of dopamine-like signalling and normalise function in the striatum in Parkinson’s disease.

Background: L-Dopa is the mainstay therapy for treating Parkinson’s disease, however, its duration of effectiveness without side effects is limited to 5-10 years in most people. Much focus has been on smoothing L-Dopa blood levels to presumably stabilise slow fluctuations in brain dopamine levels thought to become prominent as the disease progresses. This approach is successful in select groups of people. However, we hypothesised that improved treatment requires natural patterns of dopamine receptor activation, involving short, phasic events on a background of low tonic levels of dopamine activity. Such phasic activity has been shown to reinforce motor circuits, with a critical temporal conjunction between cortical activity and dopamine release. Thus, inappropriate timing of the dopamine signal following prolonged L-Dopa treatment could reinforce unwanted movements and lead to dyskinesias. We aimed to design technology to emulate the natural dopamine release pattern and evaluate its efficacy in animal models.

Methods: We developed a liposome-based system to carry dopamine receptor agonists systemically to therapeutic target areas. Coupled with a brain non-invasive controller system, we applied electrophysiology, electrochemistry and behavioural approaches to measure agonist release and evaluate cellular effects in target areas in the rat. We have also developed a sheep neurotoxin model, that will allow scale-up to an animal with a similar brain architecture to humans.

Results: We have obtained proof-of-concept of excitatory and neuromodulator effects of phasic receptor activation in striatal spiny neurons recorded in vitro. We have also demonstrated in vivo proof-of-concept of apomorphine release in urethane-anaesthetised rats. Finally, we obtained preliminary data on dopamine-agonist release in behaving animals.

Conclusions: Our preliminary work established proof-of-concept that our system releases dopamine agonists on behaviourally-relevant timescales. Ongoing work will scale up this system to a large animal model of Parkinson’s disease and determine efficacy at restoring normal movement.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/emulating-the-natural-timing-of-dopamine-receptor-activation-in-parkinsons-disease/