raclopride and Obsessive-Compulsive-Disorder

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

Changes in D(2) receptors during antidepressant therapy have been reported in patients with major depressive disorder using PET/SPET. The aim of this study was to evaluate modifications in D(2) receptors that might occur in patients affected by obsessive-compulsive disorder (OCD) during serotonin reuptake sites inhibitors (SSRIs). To this purpose, we measured the in vivo binding of [(11)C]raclopride ([(11)C]Rac)in the brain of a group of OCD naïve patients before and after the repeated administration of the inhibitor SSRI fluvoxamine. Eight patients with a Diagnostic and Statistical Manual of Mental Disorders IVth edition diagnosis of OCD completed the study undergoing a PET scan and a complete clinical evaluation before and during treatment with fluvoxamine. Patients have been compared also with a group of nine age-matched normal volunteers. Fluvoxamine treatment significantly improved clinical symptoms and increased [(11)C]Rac binding potential (BP) in the basal ganglia of OCD patients (7.5+/-5.2, 6.9+/-6.9, and 9.9+/-9.3% in dorsal caudate, dorsal putamen, and ventral basal ganglia, respectively; p<0.01) to values closer to those observed in the group of normal subjects. Chronic treatment with fluvoxamine induces a slight but significant increase in striatal [(11)C]Rac BP of previously drug-naïve OCD patients. The modifications in D(2) receptor availability might be secondary to fluvoxamine effects on serotoninergic activity.

Topics: Adult; Basal Ganglia; Brain Mapping; Carbon Isotopes; Dopamine Antagonists; Female; Fluvoxamine; Humans; Male; Middle Aged; Obsessive-Compulsive Disorder; Positron-Emission Tomography; Protein Binding; Raclopride; Receptors, Dopamine D2; Selective Serotonin Reuptake Inhibitors; Tissue Distribution

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

Repeated injections of the D2/D3 dopamine agonist, quinpirole, induce locomotor sensitization and compulsive checking behavior in rats, a phenomenon that may constitute an animal model of obsessive- compulsive disorder (OCD). Considering that the co-joint treatment with quinpirole and the kappa opioid receptor agonist U69593 potentiates locomotor sensitization to quinpirole, the present study examined whether such co-stimulation of kappa and dopamine receptors also enhances compulsive checking and whether dopamine receptor supersensitivity mediates the augmentation effects. Results showed that co-treatment of quinpirole and U69593 had a robust accelerating effect on the acquisition of sensitized locomotion and compulsive checking but that the effects on the expression of quinpirole sensitization were behavior dependent, with increased magnitude of locomotion but not of compulsive checking. Quinpirole and even U69593, which by itself did not induce sensitization, increased the proportion of dopamine D2 receptors in the high-affinity state (D2(High)) in the nucleus accumbens and striatum, indicating that elevation of D2(High) is not sufficient to account for sensitization or compulsive checking. The animal model findings point to a potential role of kappa opioid systems in hastening the pathogenesis of OCD and to the possibility that distinct brain regions may mediate the development and the expression of compulsive checking.

Topics: Algorithms; Animals; Benzazepines; Benzeneacetamides; Domperidone; Dopamine Agonists; Dopamine Antagonists; Hyperkinesis; Kinetics; Ligands; Male; Motor Activity; Obsessive-Compulsive Disorder; Pyrrolidines; Quinpirole; Raclopride; Rats; Rats, Long-Evans; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Opioid, kappa; Stereotyped Behavior