Presynaptic Dopaminergic Nerve Terminals Research Articles

Smoking‐responsive juvenile‐onset Parkinsonism

We describe a patient with juvenile levodopa-responsive Parkinsonism who reported a dramatic response to cigarette smoking with transient but marked improvement of motor symptoms associated with oculogyric crises and psychotic behavior. His beta-CIT single-photon emission computed tomography scan showed a complete absence of presynaptic dopaminergic nerve terminals.

Transcranial sonography and [123I]FP-CIT SPECT disclose complementary aspects of Parkinson's disease

Hyperechogenic signal of substantia nigra (SN) in transcranial sonography (TCS) and reduced striatal uptake in FP-CIT SPECT are common findings in idiopathic Parkinson's disease (PD). But so far it is unknown whether the extent of SN hyperechogenicity represents a correlate for the degeneration of presynaptic dopaminergic neurons in PD. We performed TCS and 123I-labelled N-(3-fluoropropyl)-2ss-carbomethoxy-3ss-(4-iodophenyl)nortropane ([123I]FP-CIT) SPECT in 53 patients with PD. Striatal FP-CIT uptake was quantified by measuring the striatal/posterior lobe binding of [123I]FP-CIT. SN echogenicity was quantified by planimetric measurement of the maximum extension of hyperechogenic signals. We found no correlation between striatal FP-CIT uptake and echogenicity of the SN, neither contralateral to the clinically more affected body side (r = +0.08, P = 0.57; Pearson's correlation) nor ipsilateral (r = +0.01; P = 0.92). Our data show that the extent of SN hyperechogenicity does not correlate with the degeneration of presynaptic dopaminergic nerve terminals. Obviously SN hyperechogenicity and degeneration of presynaptic dopaminergic nerve terminals exist independently from each other and may be based on different pathomechanisms.

In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson's disease

In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson's disease

In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson's disease

Clinical symptoms of Parkinson's disease (PD) do not manifest until dopamine (DA) neuronal loss reaches a symptomatic threshold. To explore the mechanisms of functional compensation that occur in presynaptic DA nerve terminals in PD, we compared striatal positron emission tomographic (PET) measurements by using [11C]dihydrotetrabenazine ([11C]DTBZ; labeling the vesicular monoamine transporter type 2), [11C]methylphenidate (labeling the plasma membrane DA transporter), and [18F]dopa (reflecting synthesis and storage of DA). Three consecutive PET scans were performed in three-dimensional mode by using each tracer on 35 patients and 16 age-matched, normal controls. PET measurements by the three tracers were compared between subgroups of earlier and later stages of PD, between drug-naive and drug-treated subgroups of PD, and between subregions of the parkinsonian striatum. The quantitative relationships of [18F]dopa and [11]DTBZ, and of [11C]methylphenidate and [11C]DTBZ, were compared between the PD and the normal control subjects. We found that [18F]dopa Ki was reduced less than the binding potential (Bmax/Kd) for [11C]DTBZ in the parkinsonian striatum, whereas the [11C]methylphenidate binding potential was reduced more than [11C]DTBZ binding potential. These observations suggest that the activity of aromatic L-amino acid decarboxylase is up-regulated, whereas the plasma membrane DA transporter is down-regulated in the striatum of patients with PD.

Immunochemical Analysis of Vesicular Monoamine Transporter (VMAT2) Protein in Parkinson's Disease

The vesicular monoamine transporter (VMAT2) has been suggested to be an excellent marker of presynaptic dopaminergic nerve terminals in the striatum of Parkinson's disease patients based on its high level of expression and insensitivity to drugs used to treat the disease. Previousin vivoimaging and postmortem binding studies have detected a loss in striatal VMAT2 binding in Parkinson's diseased (PD) brain; however, these techniques have poor spatial resolution and may suffer from nonspecific binding of some ligands. In this study, we use novel polyclonal antibodies to distinct regions of human VMAT2 to quantify and localize the protein. Western blot analysis demonstrated marked reductions in VMAT2 immunoreactivity in putamen, caudate, and nucleus accumbens of PD brain compared to control cases. Immunohistochemistry revealed VMAT2 immunoreactive fibers and puncta that were dense throughout the striatum of control brains, but which were drastically reduced in putamen of PD brains. In PD brains the caudate showed a significant degree of sparing along the border of the lateral ventricle and the nucleus accumbens was relatively preserved. The distribution of VMAT2 in striatum and its loss in PD paralleled that of the dopamine transporter (DAT), a phenotypic marker of dopamine neurons. Thus, immunochemical analysis of VMAT2 protein provides novel and sensitive means for localizing and quantifying VMAT2 protein and nigrostriatal dopamine terminals in PD. Furthermore, the relative expression of VMAT2 compared to that of DAT may predict the differential vulnerability of dopamine neurons in PD.

Absence of MPTP-Induced Neuronal Death in Mice Lacking the Dopamine Transporter

MPTP has been shown to induce parkinsonism both in human and in nonhuman primates. The precise mechanism of dopaminergic cell death induced following MPTP treatment is still subject to intense debate. MPP+, which is the oxidation product of MPTP, is actively transported into presynaptic dopaminergic nerve terminals through the plasma membrane dopamine transporter (DAT). In this study, we used mice lacking the DAT by homologous recombination and demonstrated that the MPTP-induced dopaminergic cell loss is dependent on the presence of the DAT. For this we have used tyrosine hydroxylase immunoreactivity (TH-IR) labeling of dopamine cells of the substantia nigra compacta in wild-type, heterozygote, and homozygote mice that were given either saline or MPTP treatments (two ip injections of 30 mg/kg, 10 h apart). Our results show a significant loss of TH-IR in wild type (34.4%), less loss in heterozygotes (22.5%), and no loss in homozygote animals. Thus dopamine cell loss is related to levels of the DAT. These results shed light on the degenerative process of dopamine neurons and suggest that individual differences in developing Parkinson's disease in human may be related to differences of uptake through the DAT of a yet unidentified neurotoxin.

Complementary positron emission tomographic studies of the striatal dopaminergic system in Parkinson's disease.

To assess the relationship between striatal dopa decarboxylase capacity, D2 dopamine receptor binding, and energy metabolism in Parkinson's disease (PD). Positron emission tomographic (PET) studies of glucose and dopa metabolism and D2 dopamine receptor binding in the caudate nucleus and putamen of patients with PD at different Hoehn and Yahr (HY) stages using PET and the tracers 18F-fluorodeoxyglucose (FDG), 6-18F-fluoro-L-dopa (FDOPA), and 11C-raclopride (RACLO). Positron emission tomography research program at the Paul Scherrer Institute. Twenty patients with PD at different stages of the disease (HY stages I through IV; five patients for each stage) compared with separate groups of age-matched healthy subjects. Influx constant (Ki) for specific FDOPA uptake; uptake index ratio for RACLO binding to D2 dopamine receptors; normalized to global FDG metabolic rate for glucose consumption; and semiquantitative score for assessment of tremor, rigidity, and bradykinesia in PD. Patients with PD at HY stages I to II (hereafter HY-I-II PD) revealed reduced FDOPA metabolism, particularly in the putamen. The FDOPA uptake in the putamen and caudate nucleus declined with increasing HY staging and scoring for bradykinesia and rigidity. Putamen RACLO binding to D2 dopamine receptors was up-regulated in patients with HY-I-II PD but declined toward control values, with increasing disease severity. Putamen side-to-side asymmetries of FDOPA metabolism and RACLO binding revealed a significant correlation. Putamen FDG metabolism showed a relative increase in all patients with PD. Our results show that FDOPA, RACLO, and FDG PET measurements provide complementary information to characterize metabolic and receptor changes in the striatum of PD with different degrees of motor disability. The FDOPA uptake reflects the best motor-related pathologic features, as indicated by the significant correlation between Ki values and clinical scores. The significant association between RACLO and FDOPA in the putamen suggests that D2 dopamine receptor changes are related to the reduction of presynaptic dopaminergic nerve terminals. Putamen FDG increase is probably the result of more complex feedback mechanisms that are primarily induced by striatal dopamine deficiency.

CHOREIC MOVEMENTS IN THE MACAQUE MONKEY INDUCED BY KAINIC ACID LESIONS OF THE STRIATUM COMBINED WITH L-DOPA

In order to produce choreic movements in monkeys (Macaca species), we have used the combination of unilateral kainic acid injections into the striatum and the systemic administration of L-DOPA. Two control monkeys received kainic acid injections alone and 7 were also given L-DOPA (150-300 mg/day) orally. No spontaneous involuntary movements were seen after kainic acid injection alone (over a period of 4-14 days). In the 7 monkeys that received L-DOPA 4-7 days after the kainic acid injection, in 5, whose striatal lesions were located in the rostral dorsolateral striatum, choreic movements appeared in the contralateral limbs following each dose of L-DOPA, whereas in 2 monkeys in which the lesion was large enough to occupy more than 60% of the rostral striatum, no choreic movements occurred. Preservation of some part of the striatum is therefore necessary for the generation of choreic movements. A considerable number of neurons in the rostral ventromedial putamen, which escaped the kainic acid lesion showed burst discharges when L-DOPA was administered. These were not seen in the caudate nucleus. The burst discharges recorded from some neurons were time-locked to the choreic movements. Since deafferentiation by dorsal root section had no effect, these burst discharges appeared to be generated in the unlesioned striatum during the choreic movements. Brains of 6 monkeys were analysed biochemically for gamma-aminobutyric acid concentration, choline acetyltransferase and tyrosine hydroxylase activity, and spiroperidol binding. Concentrations of gamma-aminobutyric acid, choline acetyltransferase activity and spiroperidol binding in the basal ganglia did not correlate with the generation of choreic movements. A finding which appeared to have a clear correlation was an increase in excess of 50% in tyrosine hydroxylase activity in the rostral ventromedial striatum on the lesioned side which escaped the kainic acid lesion in choreic monkeys as compared with the corresponding area on the intact side. It is, therefore, assumed that certain populations of 'activated' nigrostriatal dopaminergic neurons which innervate the unlesioned area of the striatum may be more likely to attain a level of activity, induced by L-DOPA, sufficient to produce choreic movements in the contralateral limbs. Methamphetamine, but not apomorphine, given to 2 monkeys, produced an effect that was essentially the same as that of L-DOPA. These results support the hypothesis that the 'activated' dopaminergic components in choreic monkeys are the presynaptic dopaminergic nerve terminals rather than the postsynaptic dopaminergic receptors.