We have investigated the role of globus pallidus (GP) serotonergic terminals in the development of levodopa-induced dyskinesias (LIDs) in Parkinson's disease (PD). We studied 12 PD patients without LIDs, 12 PD patients with LIDs, and 12 healthy control subjects. We used 11C-DASB positron emission tomography (PET), a marker of serotonin transporter availability, and 11C-raclopride PET to measure changes in synaptic dopamine levels following levodopa administration. PD patients without LIDs showed a significant reduction of GP serotonin transporter binding compared with healthy controls although this was within the normal range in PD patients with LIDs. Levels of GP serotonin transporter binding correlated positively with severity of dyskinesias. 11C-raclopride PET detected a significant rise in GP synaptic dopamine levels of patients with LIDs after a levodopa challenge but not in patients with a stable response. Our findings indicate that LIDs in PD are associated with higher GP serotonergic function. This increased serotonin function may result in further dysregulation of thalamocortical signals and so promote the expression of dyskinesias.
Levodopa remains the most effective oral treatment for Parkinson's disease (PD) despite the introduction of newer oral therapies. However, as the disease advances, 80% of PD patients develop fluctuating responses to levodopa accompanied by involuntary movements known as levodopa-induced dyskinesias (LIDs) (Horstink et al., 2006 and Lees et al., 1977). Progressive degeneration of nigrostriatal dopaminergic projections is the main pathologic hallmark of PD (Forno, 1996); however, degeneration of serotonergic, noradrenergic, and cholinergic neurones also occurs (German et al., 1992, Jellinger, 1991, Kish et al., 2008, Politis et al., 2010a, Politis et al., 2011, Politis et al., 2014 and Rylander et al., 2010).
Previous positron emission tomography (PET) studies have reported that serotonergic function is affected in PD but to a lesser extent compared with the loss of striatal dopaminergic function (Politis et al., 2010a). Animal lesion models of PD have suggested that serotonergic neurons play a role in the development of LIDs via the aberrant release of striatal dopamine as a false transmitter after levodopa administration (Carlsson et al., 2007, Carta et al., 2007 and Carta et al., 2010). A similar mechanism has been suggested in PD patients who received intrastriatal transplantation of fetal ventral mesencephalic tissue. These patients developed graft-induced dyskinesias that were associated with excessive serotonergic innervation within their grafts (Politis et al., 2010b and Politis et al., 2011). A recent PET study has demonstrated that relative preservation of striatal serotonergic terminals of advanced PD patients was associated with the development of LIDs (Politis et al., 2014).
Although most of the studies have focused on the striatum, other brain structures within the basal ganglia network are important in the control of movement. The internal globus pallidus (GPi) is the main output nucleus balancing excitatory activity from the direct and inhibitory activity from the indirect striatal pathways (Albin et al., 1989 and DeLong and Wichmann, 2009). Dopamine modulates these pathways by exciting the direct pathway's striatopallidal neurons via D1 receptors and by inhibiting the indirect pathway's striatopallidal neurons via D2 receptors. The GPi also receives a direct dopaminergic input from the medial substantia nigra (Parent and Cossette, 2001).
Although dopamine is a major modulatory neurotransmitter, the globus pallidus (GP) also receives serotonergic input from the dorsal raphe nucleus (Kita et al., 2007). A postmortem study with 3H-citalopram has shown increased levels of serotonin transporters (SERT) in the putamen and GP of PD patients with dyskinesias compared with PD patients without a history of dyskinesias (Rylander et al., 2010). In nigral lesion animal models of PD, levodopa exposure induced synaptic sprouting of serotonin neurons in the striatum, suggesting that the increased transporter expression reflects terminal upregulation (Rylander et al., 2010). This has since been corroborated by findings in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated marmosets (Zeng et al., 2010). However, it is unknown whether SERT and serotonin function is altered in patients with PD with LIDs.
We hypothesized that serotonin terminal function in GP would be relatively upregulated in PD with LIDs, so further dysregulating the signaling cascade in the network responsible for the control of movement. We sought to investigate this using 11C-DASB PET, a marker of SERT binding, and 11C-raclopride PET, a marker of dopamine D2 receptor availability which is influenced by rises in synaptic dopamine levels after a medication challenge with levodopa.
