Preferential loss of serotonin markers in caudate versus putamen in Parkinson's disease

Abstract

Interest in serotonergic involvement in Parkinson's disease (PD) has focussed recently on the possibility that the remaining serotonin neurons innervating striatum (caudate and putamen) might release dopamine as a 'false transmitter'--an action that could have both beneficial and harmful (e.g. promotion of levodopa-induced dyskinesias) consequences. Evidence for a brain serotonergic disturbance in PD is derived in large part from findings of decreased binding of different radioligands to the serotonin transporter (SERT), one 'marker' of serotonin neurons. However, it is not known whether the reported changes in SERT binding reflect actual changes in levels of SERT protein or whether concentrations of all serotonin markers are similarly and markedly decreased in the two striatal subdivisions. We measured levels of SERT immunoreactivity, and for comparison, protein levels of tryptophan hydroxylase (TPH; the marker synthetic enzyme) using a Western blot procedure, as well as concentrations of serotonin, its metabolite 5-hydroxyindoleacetic acid (5-HIAA), and dopamine by HPLC in post-mortem striatum of patients with PD and normal controls. Whereas concentrations of dopamine were severely decreased (caudate, -80%; putamen, -98%) and showed little (caudate) or no (putamen) overlap between individual control and patient values, levels of all four serotonin markers were less markedly reduced (-30% to -66%) with some patients having distinctly normal levels. Unlike the preferential loss of dopamine in putamen, the caudate was affected more than putamen by loss of all serotonin markers: serotonin (-66% versus -51%), 5-HIAA (-42% versus -31%), SERT (-56% versus -30%) and TPH (-59% versus -32%). Striatal serotonin concentration was similar in the subset of patients reported to have had dyskinesias versus those not reported to have had this drug complication. Previous findings of decreased SERT binding are likely explained by loss of SERT protein. Reduced striatal levels of all of the key serotonergic markers (neurotransmitter and metabolite, transporter protein, synthesizing enzyme protein) provide strong evidence for a serotonergic disturbance in PD, but with some patients affected much more than others. The more marked caudate reduction suggests that raphe neurons innervating this area are more susceptible to 'damage' than those innervating putamen and that any functional impairment caused by striatal serotonin loss might primarily involve the caudate. Questions related to the, as yet undetermined, clinical consequences in PD of a striatal serotonin deficiency (caudate: cognitive impairment?) and preservation (putamen: levodopa-induced dyskinesias?) should be addressed in prospective brain imaging and pharmacological studies.

Cholinergic activity and levodopa‐induced dyskinesia: a multitracer molecular imaging study

“…Indeed, in PD the caudate nucleus presents the combination of mild to moderate dopamine loss and scarce serotonergic fibers. Postmortem as well as recent in vivo molecular imaging studies have suggested a more marked serotonin deficiency in the caudate nucleus than in the putamen 38, 39, 43. A sustained cholinergic signaling in the caudate nucleus would therefore be necessary to maintain a levodopa‐derived dopamine release from the remaining striatal serotonin neurons.…”

Fluoxetine does not Impair Motor Function in Patients with Parkinson’s Disease: Correlation Between Mood and Motor Functions with Plasma Concentrations of Fluoxetine/ Norfluoxetine

“…Moreover, transcranial ultrasound studies have suggested an association with reduced brainstem raphe echogenicity and nigral hyperechogenicity in patients with depression preceding PD onset compared with nondepressed patients with PD [60]. As the PD disease progress, Lewy bodies occur with the rostral raphe, thalamus and limbic and cortical regions [15][16][17][18][19][20][21][22]61], which may result in the mediating of mood disturbances in PD [23][24][25][26].…”

“…In postmortem studies of patients with PD depletion of 5-HT in the caudate as well as hypothalamus and frontal cortex was reported [11][12][13][14], with preferential loss of 5-HT in the caudate compared with the putamen, but with relatively less loss of 5-HT (66%) than dopamine (98%) [15]. Imaging studies in vivo have also suggested depletion of 5-HT innervation to the striatum as measured via decreased 5-HT transporter binding [16][17][18].…”

Levodopa pharmacokinetics -from stomach to brain : A study on patients with Parkinson’s disease

“…The presynaptic mechanisms are caused by the DA neuron degeneration and there is a 70-80 % depletion of DA when PD patients start to experience PD symptoms. Serotonergic neurons are able to convert exogenous levodopa to DA and release it as a "false transmitter" giving symptom relief in PD patients (71)(72)(73)(74)(75) and even though the serotonin innervation in the striatum also is affected in PD, it is not degenerated to the same extent as for the dopaminergic neurons (89). Serotonergic neurons may therefore play a role in the converting process of exogenous levodopa to DA.…”