Acute Levodopa Administration Research Articles

Continuous long-range measurement of tonic dopamine with advanced FSCV for pharmacodynamic analysis of levodopa-induced dyskinesia in Parkinson's disease.

Levodopa, a dopamine prodrug, alleviates the motor symptoms of Parkinson's disease (PD), but its chronic use gives rise to levodopa-induced dyskinesia (LID). However, it remains unclear whether levodopa pharmacodynamics is altered during the progressive onset of LID. Using in vivo fast-scan cyclic voltammetry and second-derivative-based background drift removal, we continuously measured tonic dopamine levels using high temporal resolution recording over 1-h. Increases to tonic dopamine levels following acute levodopa administration were slow and marginal within the naïve PD model. However, these levels increased faster and higher in the LID model. Furthermore, we identified a strong positive correlation of dyskinetic behavior with the rate of dopamine increase, but much less with its cumulative level, at each time point. Here, we identified the altered signature of striatal DA dynamics underlying LID in PD using an advanced FSCV technique that demonstrates the long-range dynamics of tonic dopamine following drug administration.

Levodopa may modulate specific speech impairment in Parkinson's disease: an fMRI study.

Hypokinetic dysarthria (HD) is a difficult-to-treat symptom affecting quality of life in patients with Parkinson's disease (PD). Levodopa may partially alleviate some symptoms of HD in PD, but the neural correlates of these effects are not fully understood. The aim of our study was to identify neural mechanisms by which levodopa affects articulation and prosody in patients with PD. Altogether 20 PD patients participated in a task fMRI study (overt sentence reading). Using a single dose of levodopa after an overnight withdrawal of dopaminergic medication, levodopa-induced BOLD signal changes within the articulatory pathway (in regions of interest; ROIs) were studied. We also correlated levodopa-induced BOLD signal changes with the changes in acoustic parameters of speech. We observed no significant changes in acoustic parameters due to acute levodopa administration. After levodopa administration as compared to the OFF dopaminergic condition, patients showed task-induced BOLD signal decreases in the left ventral thalamus (p = 0.0033). The changes in thalamic activation were associated with changes in pitch variation (R = 0.67, p = 0.006), while the changes in caudate nucleus activation were related to changes in the second formant variability which evaluates precise articulation (R = 0.70, p = 0.003). The results are in line with the notion that levodopa does not have a major impact on HD in PD, but it may induce neural changes within the basal ganglia circuitries that are related to changes in speech prosody and articulation.

Can Dopamine Responsiveness Be Predicted in Parkinson's Disease Without an Acute Administration Test?

Dopamine responsiveness (dopa-sensitivity) is an important parameter in the management of patients with Parkinson's disease (PD). For quantification of this parameter, patients undergo a challenge test with acute Levodopa administration after drug withdrawal, which may lead to patient discomfort and use of significant resources. Our objective was to develop a predictive model combining clinical scores and imaging. 350 patients, recruited by 13 specialist French centers and considered for deep brain stimulation, underwent an acute L-dopa challenge (dopa-sensitivity > 30%), full assessment, and MRI investigations, including T1w and R2* images. Data were randomly divided into a learning base from 10 centers and data from the remaining centers for testing. A machine selection approach was applied to choose the optimal variables and these were then used in regression modeling. Complexity of the modelling was incremental, while the first model considered only clinical variables, the subsequent included imaging features. The performances were evaluated by comparing the estimated values and actual valuesResults:Whatever the model, the variables age, sex, disease duration, and motor scores were selected as contributors. The first model used them and the coefficients of determination (R2) was 0.60 for the testing set and 0.69 in the learning set (p < 0.001). The models that added imaging features enhanced the performances: with T1w (R2 = 0.65 and 0.76, p < 0.001) and with R2* (R2 = 0.60 and 0.72, p < 0.001). These results suggest that modeling is potentially a simple way to estimate dopa-sensitivity, but requires confirmation in a larger population, including patients with dopa-sensitivity < 30.

Striatal Oscillations in Parkinsonian Non-Human Primates

Dopamine loss in Parkinson’s disease (PD) is associated with abnormal oscillatory activity in the cortico-basal ganglia network. However, the oscillatory pattern of striatal neurons in PD remains poorly defined. Here, we analyzed the local field potentials in one untreated and five MPTP-treated non-human primates (NHP) with chronic, advanced parkinsonism. Oscillatory activities in the alpha (8–13 Hz) and low-beta (13–20 Hz) frequency bands were found in the striatum similarly to the motor cortex and globus pallidus of the NHP model of PD. Both alpha and low-beta frequency band oscillations of the striatum were highly coherent with the cortical and pallidal oscillations, confirming the presence of abnormal 8–20 Hz oscillatory activity in the cortico-basal ganglia network in parkinsonian NHPs. The reversal of parkinsonism induced by acute levodopa administration was associated with reduced 8–20 Hz oscillations in the striatum. These findings indicate that pathological oscillations at alpha and low-beta bands are also present in the striatum concordant with basal ganglia network changes in the primate model of PD.

Acute L-DOPA administration reverses changes in firing pattern and low frequency oscillatory activity in the entopeduncular nucleus from long term L-DOPA treated 6-OHDA-lesioned rats

The pathophysiology of Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID) is associated with aberrant neuronal activity and abnormal high levels of oscillatory activity and synchronization in several basal ganglia nuclei and the cortex. Previously, we have shown that the firing activity of neurons in the substantia nigra pars reticulata (SNr) is relevant in dyskinesia and may be driven by subthalamic nucleus (STN) hyperactivity. Conversely, low frequency oscillatory activity and synchronization in these structures seem to be more important in PD because they are not influenced by prolonged L-DOPA administration. The aim of the present study was to assess (through single-unit extracellular recording techniques under urethane anaesthesia) the neuronal activity of the entopeduncular nucleus (EPN) and its relationship with LID and STN hyperactivity, together with the oscillatory activity and synchronization between these nuclei and the cerebral cortex in 6-OHDA-lesioned rats that received long term L-DOPA treatment (or not). Twenty-four hours after the last L-DOPA injection the firing activity of EPN neurons in long term L-DOPA treated 6-OHDA-lesioned rats was more irregular and bursting compared to sham rats, being those alterations partially reversed by the acute challenge of L-DOPA. No correlation between EPN neurons firing activity and abnormal involuntary movements score was found. However, there was a significant correlation between the firing activity parameters of EPN and STN neurons recorded from long term L-DOPA treated 6-OHDA-lesioned rats. Low frequency oscillatory activity and synchronization both within the EPN and with the cerebral cortex were enhanced in 6-OHDA-lesioned animals. These changes were reversed by the acute L-DOPA challenge only in long term L-DOPA treated 6-OHDA-lesioned rats. Altogether, these results obtained from long term L-DOPA treated 6-OHDA-lesioned rats suggest (1) a likely relationship between STN and EPN firing patterns and spiking phases induced by changes after prolonged L-DOPA administration and (2) that the effect of L-DOPA on the firing pattern, low frequency oscillatory activity and synchronization in the EPN may have a relevant role in LID.

Excitability of the supplementary motor area in Parkinson's disease depends on subcortical damage

BackgroundCortical dysfunctioning significantly contributes to the pathogenesis of motor symptoms in Parkinson's disease (PD). ObjectiveWe aimed at testing whether an acute levodopa administration has measurable and specific cortical effects possibly related to striatal dopaminergic deficit. MethodsIn thirteen PD patients, we measured the electroencephalographic responses to transcranial magnetic stimulation (TMS/EEG) of the supplementary motor area and superior parietal lobule (n = 8) before and after an acute intake of levodopa. We also performed a single-photon emission computed tomography and [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane to identify the more affected and the less affected brain side in each patient, according to the dopaminergic innervation loss of the putamen. Cortical excitability changes before and after an acute intake of levodopa were computed and compared between the more and the less affected brain side at the single-patient as well as at the group level. ResultsWe found that levodopa intake induces a significant increase (P < 0.01) of cortical excitability nearby the supplementary motor area in the more affected brain side, greater (P < 0.025) than in the less affected brain side. Notably, cortical excitability changes nearby the superior parietal lobule were not statistically significant. ConclusionsThese results strengthen the idea that dysfunction of specific cortico-subcortical circuits may contribute to pathophysiology of PD symptoms. Most important, they support the use of navigated TMS/EEG as a non-invasive tool to better understand the pathophysiology of PD.

Beta-band oscillations in the supplementary motor cortex are modulated by levodopa and associated with functional activity in the basal ganglia.

We investigated the effect of acute levodopa administration on movement-related cortical oscillations and movement velocity in Parkinson's disease (PD). Patients with PD on and off medication and age- and sex-matched healthy controls performed a ballistic upper limb flexion movement as fast and accurately as possible while cortical oscillations were recorded with high-density electroencephalography. Patients off medication were also studied using task-based functional magnetic resonance imaging (fMRI) using a force control paradigm. Percent signal change of functional activity during the force control task was calculated for the putamen and subthalamic nucleus (STN) contralateral to the hand tested. We found that patients with PD off medication had an exaggerated movement-related beta-band (13–30 Hz) desynchronization in the supplementary motor area (SMA) compared to controls. In PD, spectral power in the beta-band was correlated with movement velocity. Following an acute dose of levodopa, we observed that the beta-band desynchronization in the SMA was reduced in PD, and was associated with increased movement velocity and increased voltage of agonist muscle activity. Further, using fMRI we found that the functional activity in the putamen and STN in the off medication state, was related to how responsive that cortical oscillations in the SMA of PD were to levodopa. Collectively, these findings provide the first direct evaluation of how movement-related cortical oscillations relate to movement velocity during the ballistic phase of movement in PD and demonstrate that functional brain activity in the basal ganglia pathways relate to the effects of dopaminergic medication on cortical neuronal oscillations during movement.

Levodopa has primarily negative influences on postural control in patients with Parkinson's disease

Patients with Parkinson's disease have better functional status and motor performance under on-drug conditions. However, the administration of levodopa leads to greater postural sway. The present study's primary objective was to determine whether this on-drug problem may be related to a lack of adjustment in postural control mechanisms and body segment rotations. Fourteen patients with Parkinson's disease and 14 controls performed two gaze-shift tasks (40° to the left and 40° to the right, at 0.125 and 0.25Hz) and a stationary gaze task in two sessions (an off-drug session and an on-drug session for the patients, and two off-drug sessions for the controls). At baseline, the “on-drug” patients indeed swayed significantly more than the controls during the gaze-shift tasks. As expected, acute L-dopa administration did not increase eye, head, neck and lower back rotation of the patients during the gaze-shift tasks. Unexpectedly, levodopa appeared to enable the patients to significantly increase the contribution of their postural control mechanisms (relative to controls) during the gaze-shift tasks. However, and as expected, this adjustment was not great enough to enable the patients to maintain their postural sway as well as the controls did. Overall, the administration of levodopa seemed to destabilize the patients – especially with regard to the lower back region. In addition, the patients used hypermetric eye rotations during the gaze-shift tasks under both off- and on-drug conditions. If they had not used these compensatory eye rotations, their unsafe behavior at the hip level might have been even more pronounced. Future research should focus on this lower back weakness.

Moderate traumatic brain injury increases the vulnerability to neurotoxicity induced by systemic administration of 6-hydroxydopamine in mice

Moderate traumatic brain injury (TBI) might increase the vulnerability to neuronal neurodegeneration, but the basis of such selective neuronal susceptibility has remained elusive. In keeping with the disruption of the blood-brain barrier (BBB) caused by TBI, changes in BBB permeability following brain injury could facilitate the access of xenobiotics into the brain. To test this hypothesis, here we evaluated whether TBI would increase the susceptibility of nigrostriatal dopaminergic fibers to the systemic administration of 6-hydroxydopamine (6-OHDA), a classic neurotoxin used to trigger a PD-like phenotype in mice, but that in normal conditions is unable to cross the BBB. Adult Swiss mice were submitted to a moderate TBI using a free weight-drop device and, 5h later, they were injected intraperitoneally with a single dose of 6-OHDA (100mg/kg). Afterwards, during a period of 4weeks, the mice were submitted to a battery of behavioral tests, including the neurological severity score (NSS), the open field and the rotarod. Animals from the TBI plus 6-OHDA group displayed significant motor and neurological impairments that were improved by acute l-DOPA administration (25mg/kg, i.p.). Moreover, the observation of the motor deficits correlates with (i) a significant decrease in the tyrosine hydroxylase levels mainly in the rostral striatum and (ii) a significant increase in the levels of striatal glial fibrillary acidic protein (GFAP) levels. On the whole, the present findings demonstrate that a previous moderate TBI event increases the susceptibility to motor, neurological and neurochemical alterations induced by systemic administration of the dopaminergic neurotoxin 6-OHDA in mice.

Effects of acute dopaminergic and serotonergic manipulations in the ACI paradigm depend on the basal valence of cognitive judgement bias in rats

Recent findings have revealed that pharmacological enhancement of dopaminergic (DA) function by the administration of a DA precursor (dihydroxy-l-phenylalanine; L-DOPA), but not the selective serotonin reuptake inhibitor (SSRI) citalopram, increases an optimism bias in humans. To test whether dopamine might play a similar role in non-human animals, in the present study, we evaluated the effects of acute injections of L-DOPA, the D2 receptor antagonist haloperidol, and the SSRI escitalopram on cognitive judgement bias of rats in the ambiguous-cue interpretation (ACI) paradigm. Three different doses of each drug were administered in a fully randomised Latin-square design, along with saline treatment as a control, 30min before the ACI tests. Initial analysis revealed that only animals treated with L-DOPA were more ‘pessimistic’ than the saline-treated controls. Neither haloperidol nor escitalopram significantly affected the cognitive judgement bias of rats. However, further analysis revealed that the effects of the tested compounds might depend on the basal cognitive judgement bias of the tested animals. When we divided the rats into ‘optimistic’ and ‘pessimistic’ groups based on their cognitive judgement bias in the drug-free state, it turned out that acute administration of L-DOPA caused a ‘pessimistic’ shift in ‘optimistic’ animals while showing no significant effects on ‘pessimists’. Acute administration of haloperidol caused a ‘pessimistic’ shift in ‘optimistic’ animals and an ‘optimistic’ shift in ‘pessimists’. Acute administration of escitalopram caused a ‘pessimistic’ shift in ‘optimistic’ animals and had no significant effects on ‘pessimists’, except that the middle tested dose rendered the rats more ‘optimistic’.

Aberrant CpG Methylation Mediates Abnormal Transcription of MAO-A Induced by Acute and Chronic L-3,4-Dihydroxyphenylalanine Administration in SH-SY5Y Neuronal Cells.

L-3,4-dihydroxyphenylalanine (L-dopa) remains the most effective drug for therapy of Parkinson's disease (PD); however, long-term use of it causes serious side effects. L-dopa-induced dyskinesia (LID) has consistently been related to L-dopa-derived excessive dopamine release, but the mechanisms have not been addressed very clear. Monoamine oxidase A (MAO-A) is one of the key enzymes in dopamine metabolism and therefore may be involved in L-dopa-induced side effects. And, epigenetic modification controls MAO-A gene transcription. To investigate the effects of L-dopa on MAO-A transcription and its underlying epigenetic mechanism, neuronal SH-SY5Y cells were treated with L-dopa for 24h (acute) and for 7-21days (chronic). Results showed that chronic L-dopa administration resulted in a dose-dependent and time-dependent downregulation of MAO-A, whereas acute L-dopa administration induced upregulation of MAO-A transcription and expression. Meanwhile, chronic L-dopa exposure induced CpG hypermethylation in MAO-A promoter, while acute L-dopa administration caused CpG hypomethylation. And, CpG demethylation resulted in reactivation of MAO-A transcription. These results indicated that aberrant CpG methylation might play a key role in MAO-A transcriptional misregulation in L-dopa administration. In addition, results showed that acute L-dopa administration induced downregulation of DNA methyltransferase 3a (DNMT3a). Transcription of ten-eleven translocation 1 (TET1) were significantly downregulated in chronic L-dopa administration. These data indicated that in chronic L-dopa administration, TET1 downregulation might mediate CpG hypermethylation, which is responsible for the downregulation of MAO-A transcription. In contrast, in acute L-dopa administration, DNMT3a downregulation might mediate hypomethylation, contributing to the MAO-A upregulation. In conclusion, our findings suggested that TET1 and DNMTs might mediate aberrant CpG methylation, associated with the misregulation of MAO-A in L-dopa administration, which might contribute to dopamine release abnormally leading to the side effects of L-dopa.

Dissociation of metabolic and hemodynamic levodopa responses in the 6-hydroxydopamine rat model

Dissociation of vasomotor and metabolic responses to levodopa has been observed in human subjects with Parkinson's disease (PD) studied with PET and in autoradiograms from 6-hydroxydopamine (6-OHDA) rat. In both species, acute levodopa administration was associated with increases in basal ganglia cerebral blood flow (CBF) with concurrent reductions in cerebral metabolic rate (CMR) for glucose in the same brain regions. In this study, we used a novel dual-tracer microPET technique to measure CBF and CMR levodopa responses in the same animal. Rats with unilateral 6-OHDA or sham lesion underwent sequential 15O-water (H215O) and 18F-fluorodeoxyglucose (FDG) microPET to map CBF and CMR following the injection of levodopa or saline. A subset of animals was separately scanned under ketamine/xylazine and isoflurane to compare the effects of these anesthetics. Regardless of anesthetic agent, 6-OHDA animals exhibited significant dissociation of vasomotor (ΔCBF) and metabolic (ΔCMR) responses to levodopa, with stereotyped increases in CBF and reductions in CMR in the basal ganglia ipsilateral to the dopamine lesion. No significant changes were seen in sham-lesioned animals.These data faithfully recapitulate analogous dissociation effects observed previously in human PD subjects scanned sequentially during levodopa infusion. This approach may have utility in the assessment of new drugs targeting the exaggerated regional vasomotor responses seen in human PD and in experimental models of levodopa-induced dyskinesia.

Acute Levodopa challenge for Diagnostic and Therapeutic purposes in elderly patients with Newly diagnosed Parkinsonian Syndrome

Acute Levodopa challenge for Diagnostic and Therapeutic purposes in elderly patients with Newly diagnosed Parkinsonian Syndrome

Limitations of the use of the MP-RAGE to identify neural changes in the brain: recent cigarette smoking alters gray matter indices in the striatum.

Limitations of the use of the MP-RAGE to identify neural changes in the brain: recent cigarette smoking alters gray matter indices in the striatum.

Alpha and beta EEG power reflects L-dopa acute administration in parkinsonian patients.

Aim: To evaluate the effect of an acute L-dopa administration on eye-closed resting state electroencephalographic (EEG) activity of cognitively preserved Parkinsonian patients.Methods: We examined 24 right-handed patients diagnosed as uncomplicated probable Parkinson’s disease (PD). Each patient underwent Unified Parkinson’s Disease Rating Scale (UPDRS)-part-III evaluation before and 60 min after an oral load of L-dopa-methyl-ester/carbidopa 250/25 mg. Resting condition eyes-closed EEG data were recorded both pre- and post L-dopa load. Absolute EEG power values were calculated at each scalp derivation for Delta, Theta, Alpha and Beta frequency bands. UPDRS scores (both global and subscale scores) and EEG data (power values of different frequency bands for each scalp derivation) were submitted to a statistical analysis to compare Pre and Post L-Dopa conditions. Finally, a correlation analysis was carried out between EEG spectral content and UPDRS scores.Results: Considering EEG power spectral analysis, no statistically significant differences arose on Delta and Theta bands after L-dopa intake. Conversely, Alpha and Beta rhythms significantly increased on centro-parietal scalp derivations, as a function of L-dopa administration. Correlation analysis indicated a significant negative correlation between Beta power increase on centro-parietal areas and UPDRS subscores (Rigidity of arms and Bradykinesia). A minor significant negative correlation was also found between Alpha band increase and resting tremor.Conclusions: Assuming that a significant change in EEG power spectrum after L-dopa intake may be related to dopaminergic mechanisms, our findings are consistent with the hypothesis that dopaminergic defective networks are implicated in cortical oscillatory abnormalities at rest in non-demented PD patients.

Chronic l-DOPA treatment attenuates behavioral and biochemical deficits induced by unilateral lactacystin administration into the rat substantia nigra

The aim of the study was to determine whether the dopamine (DA) precursor l-DOPA attenuates parkinsonian-like symptoms produced by the ubiquitin-proteasome system inhibitor lactacystin. Wistar rats were injected unilaterally with lactacystin (2.5μg/2μl) or 6-OHDA (8μg/2μl) into the substantia nigra (SN) pars compacta. Four weeks after the lesion, the animals were treated chronically with l-DOPA (25 or 50mg/kg) for two weeks. During l-DOPA treatment, the lactacystin-treated rats were tested for catalepsy and forelimb asymmetry. Rotational behavior was evaluated after apomorphine (0.25mg/kg) and l-DOPA in both PD models. After completion of experiments, the animals were killed and the levels of DA and its metabolites in the striatum and SN were assayed. We found that acute l-DOPA administration effectively decreased catalepsy and increased the use of the compromised forelimb in the cylinder test. However, the lactacystin group did not respond to apomorphine or acute l-DOPA administration in the rotational test. Repeated l-DOPA treatment produced contralateral rotations in both PD models, but the number of rotations was much greater in the 6-OHDA-lesioned rats. Both toxins markedly (>90%) reduced the levels of DA and its metabolites in the striatum and SN, while l-DOPA diminished these decreases, especially in the SN. By demonstrating the efficacy of l-DOPA in several behavioral tests, our study confirms the usefulness of the lactacystin lesion as a model of PD. However, marked differences in the rotational response to apomorphine and l-DOPA suggest different mechanisms of neurodegeneration evoked by lactacystin and 6-OHDA.

Central pain modulation after subthalamic nucleus stimulation

To investigate the acute effect of subthalamic nuclei deep brain stimulation (STN-DBS) and levodopa on pain and tolerance thresholds in patients with Parkinson disease. We hypothesized that a modification of pain threshold after STN-DBS would suggest a central modification of pain perception, whereas the absence of pain threshold change after STN-DBS would correspond to a peripheral mechanism via a decrease of painful stimuli. Nineteen patients with Parkinson disease were included in this double-blind, randomized, crossover study. Postoperatively, we evaluated pain thresholds (thermal and mechanical) and motor symptoms under 3 acute conditions: stimulation on/medication off; stimulation off/medication on; and stimulation off/medication off. We also conducted a retrospective analysis of the data prospectively recorded during the follow-up of the cohort pre- and postoperatively (Unified Parkinson's Disease Rating Scale [UPDRS] score, Hoehn and Yahr stage, equivalent levodopa daily dose, and tapping test score). We found a significant increase of pain and tolerance mechanical thresholds not only after acute STN-DBS but also after acute levodopa administration. We did not find any significant correlation between postoperative clinical pain improvement and UPDRS-III improvement after acute levodopa or STN-DBS, nor with motor complications improvement assessed with UPDRS-IV after chronic STN-DBS. No correlation was found between postoperative clinical pain improvement and mechanical pain threshold modification. Clinical pain alleviation after STN-DBS cannot be considered merely as a consequence of motor complications improvement and could be attributable to a direct central modulation of pain perception, via increased mechanical pain and tolerance thresholds.

Rhythm-specific modulation of the sensorimotor network in drug-naïve patients with Parkinson’s disease by levodopa

Brain activity during rest is characterized by slow (0.01-0.1 Hz) fluctuations of blood oxygenation level-dependent functional magnetic resonance imaging signals. These fluctuations are organized as functional connectivity networks called resting-state networks, anatomically corresponding to specific neuronal circuits. As Parkinson's disease is mainly characterized by a dysfunction of the sensorimotor pathways, which can be influenced by levodopa administration, the present study investigated the functional connectivity changes within the sensorimotor resting-state network in drug-naïve patients with Parkinson's disease after acute levodopa administration. Using a double-blind placebo-controlled design, resting-state functional magnetic resonance imaging was carried out in 20 drug-naïve patients with Parkinson's disease, immediately before and 60 min after, oral administration of either levodopa or placebo. Control resting-state functional magnetic resonance imaging data were recorded in 18 age- and sex-matched healthy volunteers. Independent component analysis was performed to extract resting-state network maps and associated time-course spectral features. At the anatomical level, levodopa enhanced the sensorimotor network functional connectivity in the supplementary motor area, a region where drug-naïve patients with Parkinson's disease exhibited reduced signal fluctuations compared with untreated patients. At the spectral frequency level, levodopa stimulated these fluctuations in a selective frequency band of the sensorimotor network. The reported effects induced by levodopa on sensorimotor network topological and spectral features confirm that the sensorimotor system is a target of acute levodopa administration in drug-naïve patients with Parkinson's disease. Moreover, while the regional changes in supplementary motor area reflect the functional improvement in motor function, the rhythm-specific modulation induced by the dopamine precursor discloses a novel aspect of pharmacological stimulation in Parkinson's disease, adding further insight to the comprehension of levodopa action.

Striatal Glutamate Release in l-DOPA-Induced Dyskinetic Animals

l-DOPA-induced dyskinesia is a common side effect developed after chronic treatment with 3,4-dihydroxyphenyl-l-alanine (l-DOPA) in Parkinson's disease. The biological mechanisms behind this side effect are not fully comprehended although involvement of dopaminergic, serotonergic, and glutamatergic systems has been suggested. The present study utilizes in vivo amperometry to investigate the impact from unilateral 6-hydroxydopamine lesions and l-DOPA (4 mg/kg, including benserazide 15 mg/kg) -induced dyskinetic behavior on striatal basal extracellular glutamate concentration and potassium-evoked glutamate release in urethane-anesthetized rats. Recordings were performed before and after local l-DOPA application in the striatum. In addition, effects from the 5-HT1A receptor agonist (2R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OHDPAT; 1 mg/kg) was assessed on glutamate release and on dyskinetic behavior. The results revealed a bilateral ∼30% reduction of basal extracellular glutamate concentration and attenuated potassium-evoked glutamate release after a unilateral dopamine-depletion in l-DOPA naïve animals. In dyskinetic subjects, basal glutamate concentration was comparable to normal controls, although potassium-evoked glutamate release was reduced to similar levels as in drug naïve dopamine-lesioned animals. Furthermore, acute striatal l-DOPA administration attenuated glutamate release in all groups, except in the dopamine-lesioned striatum of dyskinetic animals. Co-administration of 8-OHDPAT and l-DOPA decreased dyskinesia in dopamine-lesioned animals, but did not affect potassium-evoked glutamate release, which was seen in normal animals. These findings indicate altered glutamate transmission upon dopamine-depletion and dyskinesia.

Measuring dopaminergic function in the 6-OHDA-lesioned rat: a comparison of PET and microdialysis.

Background[18 F]fluorodopa (FDOPA) positron emission tomography (PET) allows assessment of levodopa (LDOPA) metabolism and is widely used to study Parkinson's disease. We examined how [18 F]FDOPA PET-derived kinetic parameters relate the dopamine (DA) and DA metabolite content of extracellular fluid measured by microdialysis to aid in the interpretation of data from both techniques.Methods[18 F]FDOPA PET imaging and microdialysis measurements were performed in unilaterally 6-hydroxydopamine-lesioned rats (n = 8) and normal control rats (n = 3). Microdialysis testing included baseline measurements and measurements following acute administration of LDOPA. PET imaging was also performed using [11C]dihydrotetrabenazine (DTBZ), which is a ligand for the vesicular monoamine transporter marker and allowed assessment of denervation severity.ResultsThe different methods provided highly correlated data. Lesioned rats had reduced DA metabolite concentrations ipsilateral to the lesion (p < 0.05 compared to controls), with the concentration being correlated with FDOPA's effective distribution volume ratio (EDVR; r = 0.86, p < 0.01) and DTBZ's binding potential (BPND; r = 0.89, p < 0.01). The DA metabolite concentration in the contralateral striatum of severely (>80%) lesioned rats was lower (p < 0.05) than that of less severely lesioned rats (<80%) and was correlated with the ipsilateral PET measures (r = 0.89, p < 0.01 for BPND) but not with the contralateral PET measures. EDVR and BPND in the contralateral striatum were not different from controls and were not correlated with the denervation severity.ConclusionsThe demonstrated strong correlations between the PET and microdialysis measures can aid in the interpretation of [18 F]FDOPA-derived kinetic parameters and help compare results from different studies. The contralateral striatum was affected by the lesioning and so cannot always serve as an unaffected control.