Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson's disease patients

Abstract

Levodopa-induced dyskinesias (LIDs) are the most common and disabling adverse motor effect of therapy in Parkinson's disease (PD) patients. In this study, we investigated serotonergic mechanisms in LIDs development in PD patients using 11C-DASB PET to evaluate serotonin terminal function and 11C-raclopride PET to evaluate dopamine release. PD patients with LIDs showed relative preservation of serotonergic terminals throughout their disease. Identical levodopa doses induced markedly higher striatal synaptic dopamine concentrations in PD patients with LIDs compared with PD patients with stable responses to levodopa. Oral administration of the serotonin receptor type 1A agonist buspirone prior to levodopa reduced levodopa-evoked striatal synaptic dopamine increases and attenuated LIDs. PD patients with LIDs that exhibited greater decreases in synaptic dopamine after buspirone pretreatment had higher levels of serotonergic terminal functional integrity. Buspirone-associated modulation of dopamine levels was greater in PD patients with mild LIDs compared with those with more severe LIDs. These findings indicate that striatal serotonergic terminals contribute to LIDs pathophysiology via aberrant processing of exogenous levodopa and release of dopamine as false neurotransmitter in the denervated striatum of PD patients with LIDs. Our results also support the development of selective serotonin receptor type 1A agonists for use as antidyskinetic agents in PD.

Figure 1. PET imaging and clinical studies.

Figure 2. ¹¹C-DASB and ¹¹C-raclopride PET competition studies with levodopa and buspirone, and clinical assessments, in PD stable (n = 12) and PD LIDs (n = 24) patients.

(A) No significant differences in caudate and putamen mean ¹¹C-DASB BP_ND values between the PD stable and PD LIDs groups. (B and C) ¹¹C-raclopride PET competition studies in the PD stable (B) and PD LIDs (C) groups, showing mean ¹¹C-raclopride BP_ND values OFF medication and after challenge with levodopa, with or without 0.35 mg/kg buspirone pretreatment. (D and E) Mean AIMS (D) and UPDRS-III (E) scores in PD LIDs patients recorded while OFF medication and for 150 minutes after levodopa administration, with or without 0.35 mg/kg buspirone pretreatment. (F) Correlations between higher caudate and putamen ¹¹C-DASB BP_ND values and higher decreases in percent reductions in caudate and putamen ¹¹C-raclopride BP_ND after buspirone pretreatment in PD LIDs patients. Data represent mean + SD. *P < 0.05, **P < 0.01, ***P < 0.001.

Figure 3. Individual AIMS scores for PD patients with LIDs (n = 24) after levodopa administration.

12 subjects were below (gray lines) and 12 above (black lines) the discriminating mean (blue dotted line) and median (red dotted line) cutoff for categorization into PD MM LIDs (S1–S12) and PD MS LIDs (S13–S24) groups.

Figure 4. ¹¹C-DASB and ¹¹C-raclopride PET competition studies with levodopa and buspirone, and clinical assessments, in PD MM LIDs and PD MS LIDs patients (n = 12 per group).

(A) Caudate and putamen mean ¹¹C-DASB BP_ND values in normal control, PD stable, PD MM LIDs, and PD MS LIDs groups. (B and C) ¹¹C-raclopride PET competition studies in PD MM LIDs (B) and PD MS LIDs (C) groups showing mean ¹¹C-raclopride BP_ND values OFF medication and after levodopa challenge, with or without 0.35 mg/kg buspirone pretreatment. (D–G) Mean AIMS (D and E) and UPDRS-III (F and G) scores in PD MM LIDs (D and F) and PD MS LIDs (E and G) patients OFF medication and for 150 minutes after levodopa challenge, with or without 0.35 mg/kg buspirone pretreatment. Data represent mean + SD. *P < 0.05, **P < 0.01, ***P < 0.001.

Figure 5. Significant correlations between clinical and PET imaging data in the PD MM LIDs group (n = 12).

(A) Higher putamen ¹¹C-DASB BP_ND values correlated with higher maximum and average AIMS scores during the 150-minute period after levodopa administration. (B) Higher decreases in percent reductions of putamen ¹¹C-raclopride BP_ND values (corrected for ¹¹C-DASB BP_ND values) correlated with higher maximum and average improvements in AIMS scores during the 150-minute period after buspirone pretreatment.

Figure 6. Examples of PET images, corregistered and fused with 1.5-Tesla MRI images at the level of dorsal basal ganglia, showing BP_ND values for PD patients and normal controls.

(A) ¹¹C-DASB PET images for a normal individual (62-year-old healthy male; caudate BP_ND, 1.27; putamen BP_ND, 1.32), a PD stable patient (65-year-old male with 5 years of disease; UPDRS-III score OFF medication, 26; daily LED, 410; caudate BP_ND, 0.96; putamen BP_ND, 1.14), a PD MM LIDs patient (63-year-old male with 9 years of disease; UPDRS-III score OFF medication, 40; daily LED, 987; caudate BP_ND, 0.94; putamen BP_ND, 1.17), and a PD MS LIDs patient (61-year-old male with 13 years of disease; UPDRS score OFF medication, 51; daily LED, 1,025; caudate BP_ND, 0.78; putamen BP_ND, 0.89). (B) ¹¹C-raclopride images for a normal individual (66-year-old healthy male; caudate BP_ND, 2.34; putamen BP_ND, 2.95) and for a PD MM LIDs patient (62-year-old male with 10 years of disease; UPDRS-III score OFF medication, 39; daily LED, 897), at baseline OFF medication (caudate BP_ND, 2.16; putamen BP_ND, 2.87), after levodopa administration (caudate BP_ND, 1.93; putamen BP_ND, 2.18), and after levodopa preceded by 0.35 mg/kg buspirone (caudate BP_ND, 2.07; putamen BP_ND, 2.76). Color bars show BP_ND range for ¹¹C-DASB (0–3 scale) and ¹¹C-raclopride (0–4 scale).