What is the role of biochemistry in the pathophysiology of Tourette syndrome (TS)?

Updated: May 30, 2019
  • Author: William C Robertson, Jr, MD; Chief Editor: Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP  more...
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Abnormalities of central neurotransmitters have been implicated as a cause of TS. Limited post mortem studies have shown low brainstem serotonin, low levels of glutamate in the globus pallidus, and low levels of cyclic adenosine monophosphate (AMP) in the cortex.

Affected individuals have also been shown to have an increased rate of binding of 3H-mazindol to the presynaptic dopamine-uptake-carrier sites. This observation has led some investigators to conclude that TS results from dopaminergic hyperinnervation of the ventral striatum and associated limbic system. Several studies using single-photon emission computed tomography (SPECT) have found an increase in the density of the presynaptic dopamine transporter and the postsynaptic D2 dopamine receptor.

Some neuropathological studies have supported these findings. TS may therefore result from abnormal regulation of dopamine uptake and release.

Noradrenergic pathways have also been studied, in part because tics may improve with the centrally acting alpha2-noradrenergic agonist clonidine. [11] However, studies have failed to demonstrate abnormal concentrations of norepinephrine or its metabolites in serum, cerebrospinal fluid (CSF), or urine in patients with TS.

Serotonin's role in TS remains controversial. Patients have been found to have lower plasma tryptophan levels than normal [12] and some postmortem studies have shown reduced brain tryptophan concentrations.

Unconfirmed results suggest a possible genetic link between TS and a serotonin metabolic enzyme. [13] A [123 I]b-CIT SPECT study suggested lower serotonin transporter binding in patients with TS that seemed to have an inverse correlation with clinical severity. [14] However, the relevance of these findings is unknown. Serotonin-3 receptor genes showed no clear abnormalities in TS. [15]

Most treatments that modify serotonin function (eg, fluoxetine therapy, tryptophan depletion therapy) have not produced consistent responses. However, a double-blind randomized controlled trial of the serotonin-3 receptor antagonist drug ondansetron did suggest efficacy. [16]

Other transmitter systems that may provide insights into tic production include cannabinoid/anandamide receptors, which are located densely in internal globus pallidus (among other areas). Evidence supports the efficacy of cannabinoids in reducing tic severity in some patients. [17]

Gamma-aminobutyric acid (GABA) is the most common inhibitory transmitter in the brain. Several studies have shown no abnormalities in patients with TS relative to control subjects.

The role of glutamate, the brain's predominant excitatory transmitter, needs further study. One postmortem report showed markedly different glutamate levels in the internal segment of globus pallidus (GPi), but this finding awaits confirmation. A transgenic mouse model has shown increased stereotypic activity at rest, which was worsened by administration of the noncompetitive glutamate N -methyl-D-aspartate (NMDA) receptor antagonist MK-801, which is similar to phencyclidine. [18]

The GABA-ergic striatal medium spiny neurons use enkephalin and dynorphin as cotransmitters. Although occasional patients seem to benefit from opioid agonists or antagonists, the data remain sparse. CSF dynorphin concentrations are normal in individuals with TS. [19] One small positron emission tomographic (PET) study demonstrated changes in opioid receptor binding in TS; this remains an interesting area for research. [20]

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