High Presynaptic Dopaminergic Activity in Children With Tourette's Disorder

Ernst, Monique; Zametkin, Alan J.; Jons, Peter H.; Matochik, John A.; Pascualvaca, Daisy M.; Cohen, Robert M.

doi:10.1097/00004583-199901000-00024

Cited by 110 publications

(44 citation statements)

References 49 publications

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“…This increased release, coupled with other yet-tobe-determined factors, may account for the motor and vocal tic activity of TS. Another consequence of the chronically lower tonic DA is that it may explain presynaptic upregulation of enzymes such as elevated DOPA decarboxylase and other precursors of DA; this is apparently true in SCZ (Reith et al, 1994) and perhaps in TS as well (Ernst et al, 1999). Another potential factor that could contribute to the increase in DA rel observed here would be an increase in the DA innervation.…”

Section: Discussionmentioning

confidence: 73%

Mechanisms of Dopaminergic and Serotonergic Neurotransmission in Tourette Syndrome: Clues from an In Vivo Neurochemistry Study with PET

Wong

Brašić

Singer

et al. 2007

Neuropsychopharmacol

233

172

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Tourette syndrome (TS) is a neuropsychiatric disorder with childhood onset characterized by motor and phonic tics. Obsessivecompulsive disorder (OCD) is often concomitant with TS. Dysfunctional tonic and phasic dopamine (DA) and serotonin (5-HT) metabolism may play a role in the pathophysiology of TS. We simultaneously measured the density, affinity, and brain distribution of dopamine D 2 receptors (D 2 -R's), dopamine transporter binding potential (BP), and amphetamine-induced dopamine release (DA rel ) in 14 adults with TS and 10 normal adult controls. We also measured the brain distribution and BP of serotonin 5-HT 2A receptors (5-HT 2A R), and serotonin transporter (SERT) BP, in 11 subjects with TS and 10 normal control subjects. As compared with controls, DA rel was significantly increased in the ventral striatum among subjects with TS. Adults with TS + OCD exhibited a significant D 2 -R increase in left ventral striatum. SERT BP in midbrain and caudate/putamen was significantly increased in adults with TS (TS + OCD and TS-OCD). In three subjects with TS + OCD, in whom D 2 -R, 5-HT 2A R, and SERT were measured within a 12-month period, there was a weakly significant elevation of DA rel and 5-HT 2A BP, when compared with TS-OCD subjects and normal controls. The current study confirms, with a larger sample size and higher resolution PET scanning, our earlier report that elevated DA rel is a primary defect in TS. The finding of decreased SERT BP, and the possible elevation in 5-HT 2A R in individuals with TS who had increased DA rel , suggest a condition of increased phasic DA rel modulated by low 5-HT in concomitant OCD.

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Section: Discussionmentioning

confidence: 73%

Mechanisms of Dopaminergic and Serotonergic Neurotransmission in Tourette Syndrome: Clues from an In Vivo Neurochemistry Study with PET

Wong

Brašić

Singer

et al. 2007

Neuropsychopharmacol

233

172

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“…In a PET study, 11 adolescents with TS accumulated [ 18 F] fluorodopa at a level 25% higher in the left caudate nucleus and 53% higher in the right midbrain compared with levels in control subjects. 99 The authors suggest that an up-regulation of dopa decarboxylase activity could explain these alterations and that the process reflects deficits in a variety of functional elements of the dopamine system. Nevertheless, a previous study of imaging with [ 18 F] fluorodopa showed no abnormality in presynaptic dopamine function in 10 patients with TS compared with normal subjects.…”

Section: Dopaminementioning

confidence: 99%

Current issues in Tourette syndrome

Singer

2000

Mov. Disord.

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“…The first visualization of ''dopamine'' in the living human brain was performed by the same group in 1983 [Garnett et al, 1983]. Since that first study, the FDOPA PET technique has been successfully applied to the assessment of dopamine terminals in neuropsychiatric disorders such as PD [Calne et al, 1997] and its treatment [Hagell et al, 2002], mania [Yatham et al, 2002], schizophrenia [Hietala et al, 1999], autism [Ernst et al, 1997], attention deficit hyperactivity disorder (ADHD) [Ernst et al, 1999a], Tourette's syndrome [Ernst et al, 1999b], and drug abuse [Wu et al, 1997]. One important disadvantage of FDOPA, however, arises from the fact that it is such an excellent analog of L-DOPA that it undergoes all the metabolic steps of L-DOPA.…”

mentioning

confidence: 99%

Positron‐labeled DOPA analogs to image dopamine terminals

DeJesus

2003

Drug Development Research

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Altered dopamine function has been implicated in disorders such as Parkinson's disease (PD) and other motor disorders, schizophrenia, substance abuse, attention deficit disorder, and other neuropsychiatric diseases. A useful approach to the development of PET imaging agents for dopamine terminals is to target the enzymes involved in dopamine biosynthesis. Tyrosine hydroxylase (TH) converts dietary L-p-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), which is the first and rate-limiting step in dopamine synthesis. Thus, a TH-targeted imaging agent would be the ideal PET tracer of dopamine neuronal activity. However, efforts to develop TH-based tracers have so far been unsuccessful. The next enzyme in dopamine synthesis is aromatic L-amino acid decarboxylase (AAAD), which converts L-DOPA to dopamine. AAAD was the first target in the development of imaging agents for dopamine neurons. The first useful AAAD PET tracer was 6-[ F]Fluoro-L-DOPA (FDOPA). Later, a practicable synthesis of L-[b-11 C]DOPA was developed. However, the adherence of these tracers to all the catabolic pathways of L-DOPA has been a disadvantage because of the contributions of labeled metabolites to PET images. Thus, alternative tracers with simpler metabolism such as fluoro-L-m-tyrosine (FMT) have been developed. PET studies in nonhuman primates have suggested that FMT is the PET imaging agent of choice for AAADcontaining neurons. Initial human studies show that this marker is useful in the assessment of AAADrelated neuropsychiatric disorders. This article discusses the origins and validation of dopamine PET tracers and delineates the similarities and differences between therapeutic drug development and radiopharmaceutical development as exemplified by studies on the dopamine system. Drug Dev. Res.

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High Presynaptic Dopaminergic Activity in Children With Tourette's Disorder

Cited by 110 publications

References 49 publications

Mechanisms of Dopaminergic and Serotonergic Neurotransmission in Tourette Syndrome: Clues from an In Vivo Neurochemistry Study with PET

Mechanisms of Dopaminergic and Serotonergic Neurotransmission in Tourette Syndrome: Clues from an In Vivo Neurochemistry Study with PET

Current issues in Tourette syndrome

Positron‐labeled DOPA analogs to image dopamine terminals

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