The objective of this project is to describe the potential antidyskinetic properties of the hormone oxytocin. Oxytocin is found in brain areas that are negatively affected in Parkinson’s disease (PD), such as the striatum. Oxytocin may reverse levodopa-induced dyskinesias by reducing the activity of a subset of neurons in the striatum. The researchers’ will test doses of oxytocin to show which may have beneficial effects against dyskinesias in a pre-clinical model.
They will remove dopamine from the brains of models to cause PD-like symptoms and then treat then with levodopa, which causes measurable dyskinesias. Researchers will treat these models with different doses of oxytocin and determine which dose may have good therapeutic potential. In addition, they will put a sampling probe into the brains to determine how oxytocin treatment causes changes in brain chemistry. In particular, they expect oxytocin will lower the activity of a particular type of neuron in the striatum that projects to another brain area called the globus pallidus. This will allow scientists to draw conclusions about the precise mechanism of action of oxytocin effects and its impact on dyskinesia.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Levodopa-based therapies remain the gold standard for PD. However, this treatment presents a major challenge for clinicians since constant treatment will inevitably lead to levodopa-induced dyskinesias. This research will aid in the development of a new approach to treating this side effect.
The researchers anticipate that they will find the best dose of oxytocin to decrease levodopa-induced dyskinesias in a Parkinson’s model. They expect that this dose will be associated with reduced neurotransmitter release in the globus pallidus. If this is correct, their next step will be to use oxytocin in a clinical setting with patients experiencing levodopa-induced dyskinesias.
We found that when we injected pre-clinical models with varying doses of oxytocin that we could reduce the severity of their l-DOPA induced dyskinesias. In exploring this question, we found that systemic oxytocin did indeed cross into the brain where it likely produced its effects. This was important because previously there had been no direct evidence of this phenomenon. Furthermore, we studied the mechanisms by which oxytocin produced these effects in brain areas associated with movement and l-DOPA-induced dyskinesias. We found that oxytocin produced numerous effects in a brain area called the striatum. There, we found that oxytocin might produce its effects in several ways: 1) by reducing “indirect pathway” signaling, 2) modifying l-DOPA to dopamine metabolism, and 3) elevating striatal glucose levels. Taken together, it appears that oxytocin may be a safe therapeutic for lowering l-DOPA induced dyskinesias in PD patients.