Unravelling the role of 5-HT2A receptor in multidimensional presentation of Tourette syndrome – SEROTOUR

The serotonin (5-HT) system's involvement in Tourette syndrome (TS) is suspected, but the relationship between 5-HT and TS symptoms remains unclear due to conflicting results. The 5-HT2A receptor is suggested as a regulating factor in TS symptom development and maintenance, supported by the efficacy of pharmacological compounds like aripiprazole, risperidone, ketanserin, and pimavanserin in treating tics and comorbidities. However, investigations into the etiological relevance of the 5-HT2A receptor in TS have yielded inconsistent results, likely due to confounding effects from medications and comorbidities. In this project, we aim to determine how abnormalities associated with the 5-HT2A receptor underpin the expression of tics and comorbid obsessive-compulsive disorders (OCD) in TS, particularly within distinct cortico-basal ganglia-thalamo-cortical circuits. To do this, we will perform a translational neuroimaging study using a hybrid system combining positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI). By coupling a clinical study in TS patients with experiments using a novel non-human primate (NHP) model of TS-like behaviors, we aim to localize and characterize 5-HT2A abnormalities in relation to tic and compulsive behavior severity using complementary approaches: comparative, correlative, and causal. Our clinical study will involve unmedicated TS patients with and without OCD, excluding those with current depressive episodes or attention deficit/hyperactivity disorder, using a highly selective 5-HT2A radiotracer ([18F]altanserin). In the NHP study, we will test the causal contribution of the 5-HT2A receptor to abnormal TS-like behaviors through systemic administrations of 2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI). Behavioral assessments in NHPs will include observation of spontaneous behaviors resembling tics and compulsive-like behaviors, as well as an approach-avoidance task to evaluate reward-seeking behavior and anxiety responses following DOI administration. NHP imaging with [18F]altanserin will localize DOI binding on 5-HT2A receptors in the brain, and rs-fMRI will characterize DOI's effects on connectivity networks during abnormal behaviors. We will also assess whether indirect dopamine-mediated mechanisms result from stimulation of 5-HT2A receptors by DOI, using the D2/3 antagonist radioligand [11C]raclopride to measure endogenous dopamine release in the brain post-DOI administration. By combining imaging results obtained with both radiotracers, we aim to distinguish brain networks directly correlated with 5-HT2A receptor binding from those influenced by dopamine levels. This project will provide substantial knowledge regarding the involvement of 5-HT2A in tics and comorbid OCD, its modulatory role on key neuronal networks inducing symptoms, and its interaction with dopamine neurotransmission. This could lead to new therapeutic strategies and personalized medicine approaches for TS patients.