Mechanisms of dopaminergic and serotonergic neurotransmission in Tourette syndrome: clues from an in vivo neurochemistry study with PET

Abstract

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.

Figure 1. Dopamine Receptor B_max and K_D in Subjects with Tourette Syndrome and Normal Controls

Receptor density (B_max)and affinity (K_D)were measured using the Transient Equilibrium Method (TEM; Farde et al, 1989), in subjects with TS and normal controls. The TEM method showed significant contrasts for B_max and K_D in the putamen, indicated by the double asterices ventral striatum. We also see weakly significant contrasts in the ventral striatum, indicated by the single asterices.

Figure 2. DA_rel in Subjects with Tourette Syndrome and Normal Controls by the SRTM and RTGA Methods

Dopamine release (DA_rel) is calculated using 2 mathematical modeling methods: the simplified reference tissue method (SRTM) (Lammerstma and Hume, 1996), and the reference tissue graphical analysis (RTGA) (Logan et al, 1996). Both methods demonstrate a significant elevation (approximately 50%) of DA_rel in the left and right ventral striatum, in subjects with Tourette syndrome (TS), as compared with normal controls. (Brackets indicate significant contrasts; p < 0.05.)

Figure 3. DAT Binding Potential in Subjects with Tourette Syndrome and Healthy Controls

No significant differences were seen in measurements of dopamine transporter (DAT) binding potential between subjects with Tourette syndrome (TS), as compared with normal controls, in any brain region (p>0.05).

Figure 4. SERT and 5HT_2AR Binding Potentials (BPs) in TS+OCD and TS−OCD Subjects, and Normal Controls

Panel A: Significant reductions (p < 0.05) were seen in serotonin transporter (SERT) BP in the midbrain, caudate, and putamen of subjects with Tourette syndrome (TS), when compared with normal controls. Panel C: No significant differences were seen in serotonin receptor (5-HT_2AR) BP between TS and normal controls (p > 0.05). Panel B: When grouped by OCD status, the TS+OCD groups displayed significant decreases in SERT BP in midbrain, as compared with normal controls (p < 0.05). Panel D: When grouped by OCD status, TS+OCD subjects showed slightly higher 5-HT_2A binding, but these results were not significant (p>0.1).

Figure 5. AMP-Induced DA_rel in TS+OCD and TS−OCD Subjects and Normal Controls, by the SRTM and RTGA Methods

Amphetamine (AMP)-induced dopamine release (DA_rel) was measured by the simplified reference tissue method (SRTM) (Lammerstma and Hume, 1996), and the reference tissue graphical analysis (RTGA) (Logan et al, 1996) in subjects with Tourette syndrome (TS), with and without obsessive-compulsive disorder (OCD), and normal controls. A significant increase in DA_rel was seen in TS+OCD, as compared with normal controls (p<0.05). Both analysis methods confirm the concept that AMP-induced DA_rel in the left ventral striatum is greater in TS+OCD > TS−OCD > normal controls.

Figure 6

Elevation of AMP-Induced DA_rel and 5-HT_2ARbinding potential (BP) in TS+OCD and TS−OCD Subjects, and Normal Controls A subset of subjects with Tourette syndrome and OCD (TS+OCD), who completed all dopamine and serotonin PET scans, were compared with the TS−OCD subjects and normal controls from the same study. In the 3 TS+OCD subjects, there was a significant elevation of DA_rel, as compared with normal controls (p=0.05) (*), and a significant elevation of 5-HT_2AR BP, as compared with the TS−OCD subjects (p=0.05) (*).

Figure 7. DA and 5-HT Dynamics in TS+OCD and TS−OCD

7A: Normal Control) In a healthy brain, 5-HT (1) levels can downregulate DA_rel (2). In turn, 5-HT can be regulated by SERT (3). The brain can regulate 5HT levels by changing SERT(3) and modulate the impact of 5-HT by altering 5HT2AR (4) levels. These compensatory mechanisms are altered in TS and TS with OCD, as shown below. B) TS patient (No OCD) In a patient with TS, we propose that the primary deficit is diminished 5HT levels (1) resulting in an upregulation of DA_rel (2). In response to diminished 5HT, SERT levels (2) decrease to compensate, allowing more 5HT to remain in the synapse, the higher intrasynaptic 5-HT in turn leads to a decrease in 5HT2AR numbers (4). C) TS Patient with OCD In a patient with both TS and OCD, SERT (1) fails to compensate, and as a result, there are substantially lower levels of 5HT(2). As a result, there is an even greater hyper-responsive DA_rel (3). Additionally, because of the lowered 5HT, there is a compensatory increase in 5HT2AR number. (4)