Neurotransmitter abnormalities in primary tic disorders and Tourette syndrome

Tourette syndrome (TS) and primary tic disorders are increasingly understood as neurodevelopmental conditions arising from dysfunction within the cortico-basal ganglia-thalamo-cortical circuits, which govern motor, cognitive, and affective processes. This chapter reviews current knowledge on the neurochemical underpinnings of TS, drawing on evidence from neuroimaging studies - notably positron emission tomography - genetics, animal models, and neuropathology. Particular emphasis is placed on the roles of dopamine, serotonin, glutamate and γ-aminobutyric acid (GABA). Dopaminergic hyperactivity, especially involving increased D2 receptor sensitivity in the striatum, has been strongly linked to tic expression. Serotonergic dysfunction, though less consistently defined, may contribute to both tics and common comorbidities such as obsessive-compulsive behaviors, anxiety, and depression. However, the exact nature of serotonin's involvement remains unresolved, complicated by the influence of comorbidities and treatment effects. Additionally, glutamate and GABA, the brain's primary excitatory and inhibitory neurotransmitters, respectively, have emerged as crucial in modulating excitatory/inhibitory balance within the cortico-basal ganglia-thalamo-cortical loops. Glutamatergic hyperactivity and GABAergic deficits may lead to the disinhibition of motor outputs, exacerbating tic symptoms, and interact synergistically with dopaminergic circuits. Taken together, these findings underscore the multifactorial and interconnected nature of neurotransmitter abnormalities in TS. Rather than stemming from a single neurochemical deficit, TS likely arises from a complex interplay between multiple systems - dopaminergic, serotonergic, glutamatergic, GABAergic, and others - converging within dysfunctional brain networks that regulate motor and behavioral control.