Using a novel animal model of the dopaminergic dysfunction of schizophrenia to trial an innovative treatment approach

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.