The mechanisms and significance of the dopaminergic and serotonergic neurotransmission systems in Tourette Syndrome (TS) have not been thoroughly investigated and explained. A more complete understanding of their roles in TS would lead to better selection of pharmacological treatments for these patients and provide insight into the pathophysiology of TS. This project will examine pre-, and post- and intrasynaptic dopamine neurotransmission DA transporter (DAT), D2 density (D2Bmax) and DA release (DArel), simultaneously in patients with TS. Serotonin abnormalities will be studied in patients with TS and obsessive-compulsive disorder (OCD), a co-morbid disease. Based on our prior neuroreceptor imaging experience with positron emission tomography (PET) in TS and other neuropsychiatric disorders, we hypothesized that DArel stimulated by an amphetamine challenge will be increased in TS and will correlate with the severity of symptoms (Aim 1).
In Aim 2 we will investigate how the relationship between the pre-, post- and intrasynaptic measures of dopamine differ between patients with TS and normal controls. For example, we predict dopamine release and D2 dopamine receptors will both be increased in TS compared to normal subjects. There is a need to establish appropriate serotonin and dopamine/serotonin combinations in the treatment of TS. We hypothesize that there are abnormal serotonin receptors and transporters in TS subjects prior to treatment and that the differences will be most pronounced in subjects with symptoms of OCD. We will examine pre-synaptic serotonin transporters(SERT) and post-synaptic (5HT24R) in TS subjects with and without OCD and compare the results to controls with and without OCD (Aim 3).
In Aim 4 we will explicitly examine the relationship of DArel together with the serotonergic measures to explore dopamine serotonin interactions in the same individual. The measurement of pre-, and post- and intrasynaptic dopaminergic parameters has never been performed simultaneously in the same TS subject. Serotonin 5HT24R and SERT have not been studied in same patients with TS and symptoms of OCD. We propose to carry out experiments using PET to establish a more complete understanding of the neurotransmission in TS. This will also help establish new ationales for improved therapeutics in TS.
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