The clinical course of Parkinson’s disease (PD) is complicated by the development of
motor and non-motor complications. This thesis, using clinical motor and non-motor
assessments and positron emission tomography (PET) imaging with 11C-raclopride, 11CDASB
and 18F-DOPA, aims to explore in PD the role of: (1) postsynaptic dopamine D2
receptor dysfunction, (2) serotonergic dysfunction in the development of non-motor
symptoms such as depression and body weight change, (3) striatal serotonergic neurons in
levodopa- and graft -induced dyskinesias (LIDs and GIDs), and (4) the efficacy of
treatment with continuous dopaminergic stimulation.
The main findings are as follows: (1) D2 receptor dysfunction in the hypothalamus but not
in the putamen was evident in PD, possibly accounting for the development of non-motor
symptoms. (2) A staging of serotonergic dysfunction throughout the clinical course of PD
has been demonstrated in this thesis and showed that serotonergic system is involved early
on. (3) Higher serotonin transporter availability has been found in PD patients with
elevated depressive symptoms and in PD patients with significant changes in their body
weight. (4) Striatal serotonergic terminals are involved in peak-dose LIDs in PD, and
administration of a high bolus dose of a 5-HT1A agonist was able to normalize extracellular
dopamine levels and alleviate dyskinesias. (5) Excessive serotonergic innervation was
found in two PD patients with GIDs who had experienced major recovery after striatal
transplantation with fetal cells. GIDs were markedly attenuated by repeated administration
of low doses of a 5-HT1A agonist, which dampens transmitter release from serotonergic
neurons, indicating that serotonergic hyperinnervation was the likely cause of GIDs. (6)
Continuous dopaminergic stimulation with levodopa intestinal gel induced good clinical
response and stable and prolonged synaptic levels of striatal dopamine release.
My observations provide fundamental insight for the role and interaction of serotonergic
and dopaminergic systems in the pathophysiology of PD and have key implications for the
management of motor and non-motor complications with drugs or cell therapies.