raclopride and Tourette-Syndrome

Tourette syndrome (TS) is a neuropsychiatric disorder with childhood onset characterized by motor and phonic tics. Obsessive-compulsive 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 D2 receptors (D2-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-HT2A receptors (5-HT2AR), 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 D2-R, 5-HT2AR, and SERT were measured within a 12-month period, there was a weakly significant elevation of DA rel and 5-HT2A 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-HT2AR 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.

Topics: Adult; Amphetamine; Brain Mapping; Dopamine; Dopamine Agents; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Magnetic Resonance Imaging; Male; Models, Theoretical; Neuropsychological Tests; Obsessive-Compulsive Disorder; Positron-Emission Tomography; Psychiatric Status Rating Scales; Raclopride; Receptors, Dopamine D2; Serotonin; Synaptic Transmission; Tourette Syndrome

Pharmacological and anatomical evidence implicates striatal dopamine receptors in Tourette syndrome (TS). Nevertheless, results of positron emission tomography (PET) studies of the dopamine system in TS have been inconsistent. We investigated striatal D2/3 dopamine receptors in TS using the radioligands [(11) C]raclopride and [(11) C]-(+)-PHNO, an agonist that binds preferentially to D3 receptors, thus allowing higher sensitivity and measurement of receptors in a high affinity state. Eleven adults with TS and 11 matched healthy control (HC) participants underwent [(11) C]raclopride and [(11) C]-(+)-PHNO PET scans. General linear model was used for voxelwise contrasts of striatal binding potentials (BPND ) between TS and HC participants. Analysis of variance was performed to investigate main effect of radioligand. In addition, BPND values were extracted for ventral, motor, and associative striatum. Finally, we examined the relationship between BPND measures and symptom severity in TS participants. Main effects analyses showed that [(11) C]-(+)-PHNO BPND was higher in ventral striatum, whereas [(11) C]raclopride BPND was higher in motor and associative striatum. There were no significant group differences between TS and HC. Furthermore, TS and HC participants had similar [(11) C]-(+)-PHNO and [(11) C]raclopride BPND in the three striatal subregions. Moreover, there was no significant correlation between BPND and symptom severity. TS and HC participants had similar striatal D2/3 receptor availability measures. These results challenge the assumption that striatal dopamine receptors have a major role in the pathophysiology of TS. Consistent with previous findings, [(11) C]-(+)-PHNO localized preferentially to ventral striatal, D3 receptor-rich regions, in contrast to [(11) C]raclopride, which localized preferentially in the dorsal striatum.

Topics: Adolescent; Adult; Corpus Striatum; Dopamine Agonists; Dopamine D2 Receptor Antagonists; Female; Humans; Male; Middle Aged; Oxazines; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3; Severity of Illness Index; Tourette Syndrome; Young Adult

Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalities of cortico-basal ganglia circuits. A mutation in histidine decarboxylase (Hdc), the key enzyme for the biosynthesis of histamine (HA), has been implicated as a rare genetic cause. Hdc knockout mice exhibited potentiated tic-like stereotypies, recapitulating core phenomenology of TS; these were mitigated by the dopamine (DA) D2 antagonist haloperidol, a proven pharmacotherapy, and by HA infusion into the brain. Prepulse inhibition was impaired in both mice and humans carrying Hdc mutations. HA infusion reduced striatal DA levels; in Hdc knockout mice, striatal DA was increased and the DA-regulated immediate early gene Fos was upregulated. DA D2/D3 receptor binding was altered both in mice and in humans carrying the Hdc mutation. These data confirm histidine decarboxylase deficiency as a rare cause of TS and identify HA-DA interactions in the basal ganglia as an important locus of pathology.

Topics: Adolescent; Adult; Amphetamine; Animals; Brain; Child; Dopamine Agonists; Dopamine Antagonists; Exploratory Behavior; Female; Histidine Decarboxylase; Humans; Male; Maze Learning; Mice; Mice, Knockout; Middle Aged; Mutation; Oxazines; Raclopride; Radionuclide Imaging; Stereotyped Behavior; Time Factors; Tourette Syndrome; Tryptophan; Young Adult

Tourette syndrome (TS) and obsessive-compulsive disorder (OCD) both are neuropsychiatric disorders associated with abnormalities in dopamine neurotransmission. Aims of this study were to quantify striatal D2/3 receptor availability in TS and OCD, and to examine dopamine release and symptom severity changes in both disorders following amphetamine challenge. Changes in [(11)C]raclopride binding potential (BP(ND)) were assessed using positron emission tomography before and after administration of d-amphetamine (0.3 mg kg(-1)) in 12 TS patients without comorbid OCD, 12 OCD patients without comorbid tics, and 12 healthy controls. Main outcome measures were baseline striatal D2/3 receptor BP(ND) and change in BP(ND) following amphetamine as a measure of dopamine release. Voxel-based analysis revealed significantly decreased baseline [(11)C]raclopride BP(ND) in bilateral putamen of both patient groups vs. healthy controls, differences being more pronounced in the TS than in the OCD group. Changes in BP(ND) following amphetamine were not significantly different between groups. Following amphetamine administration, tic severity increased in the TS group, which correlated with BP(ND) changes in right ventral striatum. Symptom severity in the OCD group did not change significantly following amphetamine challenge and was not associated with changes in BP(ND). This study provides evidence for decreased striatal D2/3 receptor availability in TS and OCD, presumably reflecting higher endogenous dopamine levels in both disorders. In addition, it provides the first direct evidence that ventral striatal dopamine release is related to the pathophysiology of tics.

Topics: Adult; Carbon Radioisotopes; Case-Control Studies; Corpus Striatum; Dextroamphetamine; Dopamine; Dopamine Antagonists; Dopamine Uptake Inhibitors; Female; Functional Neuroimaging; Humans; Male; Middle Aged; Obsessive-Compulsive Disorder; Psychiatric Status Rating Scales; Raclopride; Radionuclide Imaging; Receptors, Dopamine D2; Receptors, Dopamine D3; Tourette Syndrome

Dopaminergic abnormalities in frontal-subcortical circuits have been hypothesized as the underlying pathophysiologic mechanism in Tourette's syndrome. The objective of this study was to test the hypothesis that presynaptic dopamine release from the striatum is abnormal in adults with Tourette's syndrome.. Seven adults with Tourette's syndrome and five age-matched comparison subjects each received two positron emission tomography (PET) scans with high specific activity [11C]raclopride. The first scan followed an intravenous injection of saline; the second followed an intravenous injection of amphetamine. The relative dopamine release was estimated as the percentage difference in binding potential between the postsaline and postamphetamine scans.. Binding potential determined after the initial [11C]raclopride scan did not significantly differ between Tourette's syndrome and comparison subjects. After amphetamine challenge, the mean value of intrasynaptic dopamine in the putamen (as determined by true equilibrium bolus estimation) increased by 21% in the subjects with Tourette's syndrome and did not change in the comparison subjects; the mean values increased by 16.9% and decreased by 1.8%, respectively, when measured by the constrained method. Dopamine release in the caudate region was not significantly different in the Tourette's syndrome and comparison subjects.. Greater putamen dopamine release was seen in adults with Tourette's syndrome than in comparison subjects after a pharmacologic challenge with amphetamine. These results suggest that the underlying pathobiology in Tourette's syndrome is a phasic dysfunction of dopamine transmission.

Topics: Adult; Amphetamine; Corpus Striatum; Dopamine; Dopamine Antagonists; Humans; Injections, Intravenous; Male; Middle Aged; Putamen; Raclopride; Sodium Chloride; Synapses; Tomography, Emission-Computed; Tourette Syndrome

Dysfunction of the dopaminergic pathway has been postulated to underlie the symptomatology of Tourette's syndrome. Presynaptic functional integrity of dopaminergic terminals was assessed with 18F-dopa PET in 10 patients with Tourette's syndrome, three of whom were drug free and seven of whom were on neuroleptic treatment. Dopamine D2 receptor site density was measured with 11C-raclopride PET in a further group of five drug free patients with Tourette's syndrome. Mean caudate and putamen 18F-dopa influx constants were similar in patients with Tourette's syndrome and controls, and there was no difference in striatal 18F-dopa uptake between the treated and untreated Tourette's syndrome groups. Mean caudate and putamen 11C-raclopride binding potentials in patients with Tourette's syndrome were also similar to control values. The findings suggest that striatal metabolism of exogenous levodopa and the density of striatal D2 receptors are both normal in patients with Tourette's syndrome and that Tourette's syndrome does not arise from a primary dysfunction of dopaminergic terminals.

Topics: Adolescent; Adult; Antipsychotic Agents; Carbon Radioisotopes; Case-Control Studies; Caudate Nucleus; Dihydroxyphenylalanine; Dopamine D2 Receptor Antagonists; Female; Fluorine Radioisotopes; Humans; Levodopa; Male; Matched-Pair Analysis; Middle Aged; Presynaptic Terminals; Putamen; Raclopride; Receptors, Dopamine; Salicylamides; Tomography, Emission-Computed; Tourette Syndrome