EDiPSPrevent · Using a novel animal model of the dopaminergic dysfunction of schizophrenia to trial an innovative treatment approach
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2022-01-31 → 2024-01-30
- EU contribution
- €212,934
- Participants
- 1
- Scheme
- MSCA-IF
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Results in brief
Using a novel animal model of the dopaminergic dysfunction of schizophrenia to trial an innovative treatment approach
Schizophrenia affects around 1% of the population and leads to dramatically reduced quality of life, as well as premature mortality in many instances. The current treatments for schizophrenia – antipsychotic drugs – show some efficacy at treating the hallucinations and delusions of this disorder. However, these drugs are far from ideal, as they result in side-effects which discourage adherence, and are ineffective in around 30% of patients. Improving treatment options for schizophrenia is important for patients, but also for their carers, on whom the burden of financial and emotional support falls heavily. This disorder also results in additional economic cost via the public health system. Therefore, this fellowship had two primary objectives: - To improve our understanding of two critical models of schizophrenia-relevant neurobiology: the ketamine model, and the Enhanced Dopamine in Prodromal Schizophrenia Model - To use these models and other neurobiological techniques to understand more about a certain class of novel treatment options – trace amine-associated receptor 1 (TAAR1) agonists. As a result of this fellowship, I developed a novel method to analyse preclinical neuroimaging data, to look at the midbrain – a region which is highly implicated in schizophrenia. I then applied this method to the ketamine model of schizophrenia. I also trialled the Enhanced Dopamine in Prodromal Schizophrenia Model in mice (whereas it has been developed in rats). While these results were not conclusive, they suggest that this model can be established in mice, and this work will form the pilot data for future funding applications. Finally, I used mouse brain slices to look at the effects of a TAAR1 agonist – ulotaront on dopamine release in the striatum. Patients with schizophrenia show elevated dopamine release in this region, and therefore an effective treatment could target this dysfunction. I found that ulotaront did indeed decrease dopamine release in this region, supporting its use a novel treatment option for schizophrenia.
Data: CORDIS, © European Union
Project objective
Treatments for schizophrenia are inadequate, and intervening prior to disease onset is a novel approach to improve patient outcomes. Clinical studies using positron emission tomography (PET) have revealed that patients with chronic schizophrenia consistently show an increase in dopamine synthesis capacity in the striatum. This dysfunction is also evident in people at-risk of developing schizophrenia, specifically in those who are later diagnosed with this disorder. Normalizing this increase in pre-synaptic dopamine therefore reflects an extremely promising target for new treatments of schizophrenia. I developed a novel animal model of schizophrenia – Enhanced Dopamine in Prodromal Schizophrenia (EDiPS) – which replicates the pre-synaptic dopaminergic dysfunction seen so robustly in patients. In this project, I propose to firstly use state-of-art preclinical PET to examine pre-synaptic dopamine in EDiPS animals. This will confirm its translatability to the findings in the clinical population. Through a secondment, I will assess other key aspects of dopamine neurotransmission in these animals, focussing on the source of dopaminergic innervation to the striatum – the midbrain. As a complementary objective, I will assess any difference between male and female EDiPS animals for each of these outcomes. This is especially relevant to schizophrenia, which is a sexually dimorphic disorder. The second objective of this fellowship is to trial a novel approach to normalise the increase in pre-synaptic dopamine in EDiPS animals, through a Trace Amino Acid Receptor 1 (TAAR1) agonist. I will trial the TAAR1 agonist both acutely in adult EDiPS animals, and when given chronically during development, to simulate an intervention in the at-risk population. This will be the first study to examine the effects of a TAAR1 agonist in the developing brain. The scientific outcomes of this fellowship will have real-world implications for the treatment of patients with schizophrenia.
Original text from CORDIS.
Participants
- IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE · LondonCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union