Periodic Reporting for period 1 - HT4PD (The role of the serotonin 5-HT4 receptor in motor and non-motor symptoms of Parkinson’s disease)
Reporting period: 2021-01-01 to 2023-12-31
Parkinson’s Disease (PD) is the second most common, progressive, adult onset, neurodegenerative disease in Europe and is characterized by the loss of midbrain dopaminergic neurons and the formation of Lewy bodies in the remaining dopaminergic neurons, causing motor impairment such as bradykinesia, rigidity and slow movement. Dopamine (DA) via L-Dopa therapy ameliorates many but not all symptoms and induces uncontrollable L-Dopa induced dyskinesia (LID), a complicated and debilitating side effect that affects almost all patients following 5-10 years of chronic treatment. L-Dopa induced dyskinesia (LID) affects up to 90% of patients treated with L-DOPA and currently no treatment to ameliorate symptoms exist. There is an urgent need to better understand the pathophysiology underlying this important treatment side effect and to develop drugs to reduce symptoms.
It is known that the neurotransmitters systems of Dopamine and Serotonin interact with each other and it is known that neurons producing serotonin can also metabolize and release L-DOPA which Is thought to contribute to the L-DOPA induced dyskinesia.
We study specific serotonin receptors to better understand this functional interaction and to identify targets for pharmacotherapy aiming to alleviate the dyskinesia. We want to determine the expression pattern of serotonin receptors on a cellular level, determine how modulation thereof alters responses to the drug L-DOPA and to LID in a mouse model of Parkinson.
It is known that the neurotransmitters systems of Dopamine and Serotonin interact with each other and it is known that neurons producing serotonin can also metabolize and release L-DOPA which Is thought to contribute to the L-DOPA induced dyskinesia.
We study specific serotonin receptors to better understand this functional interaction and to identify targets for pharmacotherapy aiming to alleviate the dyskinesia. We want to determine the expression pattern of serotonin receptors on a cellular level, determine how modulation thereof alters responses to the drug L-DOPA and to LID in a mouse model of Parkinson.
We are in the process of studying the role a serotonin receptor in the context of L-DOPA induced dyskinesia and have shown that modulating receptor activity also impacts on the severity of L-DOPA induced dyskinesia.
We are currently investigating the molecular underpinnings of this functional interaction in a cell–specific context.
We have shown that pharmacological activation of 5-HT4 receptor activity reduces L-DOPA induced dyskinesia in a mouse model of Parkinson's disease. We further found that this activation does not impact negatively on the anti-akinetic effect of L-DOPA.
Using the RNAscope technology and qPCR, we show that the 5-HT4 receptor in the dorsal striatum is predominantly expressed in D2-receptor expressing medium spiny neurons (MSNs) and that its expression is enhanced in response to Dopamine depletion and L-DOPA treatment.
We therefore conclude that the anti-LID action of 5-HT4R agonssim is mediated via the D2-MSNs.
We are currently investigating the molecular underpinnings of this functional interaction in a cell–specific context.
We have shown that pharmacological activation of 5-HT4 receptor activity reduces L-DOPA induced dyskinesia in a mouse model of Parkinson's disease. We further found that this activation does not impact negatively on the anti-akinetic effect of L-DOPA.
Using the RNAscope technology and qPCR, we show that the 5-HT4 receptor in the dorsal striatum is predominantly expressed in D2-receptor expressing medium spiny neurons (MSNs) and that its expression is enhanced in response to Dopamine depletion and L-DOPA treatment.
We therefore conclude that the anti-LID action of 5-HT4R agonssim is mediated via the D2-MSNs.
This is the final report for the grant, but we plan to further investigate the role of this receptor in LID.