Levodopa Administration Research Articles

Mechanism of parkinsonian neuronal oscillations in the primate basal ganglia: some considerations based on our recent work.

Accumulating evidence suggests that abnormal neuronal oscillations in the basal ganglia (BG) contribute to the manifestation of parkinsonian symptoms. In this article, we would like to summarize our recent work on the mechanism underlying abnormal oscillations in the parkinsonian state and discuss its significance in pathophysiology of Parkinson’s disease. We recorded neuronal activity in the BG of parkinsonian monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Systemic administration of L-DOPA alleviated parkinsonian motor signs and decreased abnormal neuronal oscillations (8–15 Hz) in the internal (GPi) and external (GPe) segments of the globus pallidus and the subthalamic nucleus (STN). Inactivation of the STN by muscimol (GABAA receptor agonist) injection also ameliorated parkinsonian signs and suppressed GPi oscillations. The blockade of glutamatergic inputs to the STN by local microinjection of a mixture of 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (glutamatergic NMDA receptor antagonist) and 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (glutamatergic AMPA/kainate receptor antagonist) suppressed neuronal oscillations in the STN. STN oscillations were also attenuated by the blockade of GABAergic neurotransmission from the GPe to the STN by muscimol inactivation of the GPe. These results suggest that cortical glutamatergic inputs to the STN and reciprocal GPe-STN interconnections are both important for the generation and amplification of the oscillatory activity of GPe and STN neurons in the parkinsonian state. The oscillatory activity in the STN is subsequently transmitted to the GPi and may contribute to manifestation of parkinsonian symptoms.

1-Benzyl-1,2,3,4-tetrahydroisoquinoline, an endogenous neurotoxic compound, disturbs the behavioral and biochemical effects of L-DOPA: in vivo and ex vivo studies in the rat.

Environmental factors and endogenously produced toxins, such as 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), are considered to be involved in the pathogenesis of Parkinson’s disease (PD). In this study, we investigated the impact of single and multiple 1BnTIQ (25 and 50 mg/kg i.p.) administration on l-DOPA-induced changes in the rate of dopamine and serotonin metabolism in the rat brain. Additionally, using in vivo microdialysis, we measured the impact of acute and multiple 1BnTIQ administrations on l-DOPA-induced dopamine release in the striatum. These data were compared with results from behavioral tests in which we measured the effect of 1BnTIQ and l-DOPA on locomotor activity. Finally, we determined the effect of the repeated administration of 1BnTIQ on the l-DOPA-induced elevation of caspase-3 activity in the hippocampus. An ex vivo neurochemical study indicated that both acute and chronic 1BnTIQ injections strongly inhibited l-DOPA-induced increases in the concentration of dopamine and all of its metabolites in dopaminergic structures. In contrast, in vivo microdialysis studies suggested that the differences in 1BnTIQ’s effects are dependent on the type of treatment. A single dose of 1BnTIQ intensified the elevation of dopamine release induced by l-DOPA administration (~1,300 %; P < 0.01), while multiple administrations of 1BnTIQ significantly enhanced the basal dopamine levels while partially diminishing the effects of l-DOPA injection (~200 %; P < 0.01). Additionally, we found that chronic administration of 1BnTIQ completely blocked the l-DOPA-induced increase in caspase-3 activity in the hippocampus. These findings indicate that both acute and chronic administrations of 1BnTIQ disturbs the behavioral and biochemical effects of l-DOPA in the rat. The data presented from ex vivo and in vivo studies clearly suggest that 1BnTIQ’s effects may be connected with the inhibition of DAT and/or COMT activity in the brain. Furthermore, elevated endogenous levels of 1BnTIQ may pose a serious risk in PD patients undergoing l-DOPA therapy.

Spiral Analysis in Subjects with Parkinson's Disease before and after Levodopa Treatment: A New Protocol with Stereophotogrammetric Systems

a method for the quantification of handwritten spirals in patients with Parkinson's Disease (PD) pre and post levodopa treatment is reported. Fifteen PD patients (mean age: 66.80±9.75 years) were assessed in the absence of medication (OFF condition) and under levodopa administration (ON condition). The control group was composed of 15 age-matched healthy (H) individuals (mean age: 63.70±9.40). They were asked to hand draw a spiral at self-selected speed, without resting their forearm on the table. The participants drew on a paper sheet, using a normal pen. The trace of the pen was determined from the 3D coordinates of passive markers placed on the pen and on the sheet, acquired with an optoelectronic system and some parameters were identified and computed. the method revealed to be significant in highlighting the differences between H and PD subjects and in detecting pharmacologic effect. PD patients are impaired in spiral drawing execution and levodopa improves drawing performance, evidenced by spatio-temporal parameters and velocity profiles. The protocol is easily employable in clinic analysis because of its simplicity, the short duration of the test, and the natural test conditions. These characteristics suggest the applicability of this protocol to other fields of motor and cognitive assessments.

Derangement of Ras-Guanine Nucleotide-Releasing Factor 1 (Ras-GRF1) and Extracellular Signal-Regulated Kinase (ERK) Dependent Striatal Plasticity in L-DOPA-Induced Dyskinesia

BackgroundBidirectional long-term plasticity at the corticostriatal synapse has been proposed as a central cellular mechanism governing dopamine-mediated behavioral adaptations in the basal ganglia system. Balanced activity of medium spiny neurons (MSNs) in the direct and the indirect pathways is essential for normal striatal function. This balance is disrupted in Parkinson’s disease and in l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID), a common motor complication of current pharmacotherapy of Parkinson’s disease. MethodsElectrophysiological recordings were performed in mouse cortico-striatal slice preparation. Synaptic plasticity, such as long-term potentiation (LTP) and depotentiation, was investigated. Specific pharmacological inhibitors or genetic manipulations were used to modulate the Ras-extracellular signal-regulated kinase (Ras-ERK) pathway, a signal transduction cascade implicated in behavioral plasticity, and synaptic activity in different subpopulations of striatal neurons was measured. ResultsWe found that the Ras-ERK pathway, is not only essential for long-term potentiation induced with a high frequency stimulation protocol (HFS-LTP) in the dorsal striatum, but also for its reversal, synaptic depotentiation. Ablation of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1), a neuronal activator of Ras proteins, causes a specific loss of HFS-LTP in the medium spiny neurons in the direct pathway without affecting LTP in the indirect pathway. Analysis of LTP in animals with unilateral 6-hydroxydopamine lesions (6-OHDA) rendered dyskinetic with chronic L-DOPA treatment reveals a complex, Ras-GRF1 and pathway-independent, apparently stochastic involvement of ERK. ConclusionsThese data not only demonstrate a central role for Ras-ERK signaling in striatal LTP, depotentiation, and LTP restored after L-DOPA treatment but also disclose multifaceted synaptic adaptations occurring in response to dopaminergic denervation and pulsatile administration of L-DOPA.

Excessive cocaine use results from decreased phasic dopamine signaling in the striatum.

Drug addiction is a neuropsychiatric disorder marked by escalating drug use. Dopamine neurotransmission in the ventromedial striatum (VMS) mediates acute reinforcing effects of abused drugs, but with protracted use the dorsolateral striatum (DLS) is thought to assume control over drug seeking. We measured striatal dopamine release during a cocaine self-administration regimen that produced escalation of drug taking in rats. Surprisingly, we found that phasic dopamine decreased in both regions as the rate of cocaine intake increased; with the decrement in dopamine in the VMS significantly correlated with the rate of escalation. Administration of the dopamine precursor L-DOPA at a dose that replenished dopamine signaling in the VMS reversed escalation, thereby demonstrating the causal relationship between diminished dopamine transmission and excessive drug use. Thus, together these data provide mechanistic and therapeutic insight into the excessive drug intake that emerges following protracted use.

Sustained Increase of PKA Activity in the Postcommissural Putamen of Dyskinetic Monkeys

Levodopa-induced dyskinesias (LID) are a frequent complication of Parkinson's disease pharmacotherapy that causes significant disability and narrows the therapeutic window. Pharmacological management of LID is challenging partly because the precise molecular mechanisms are not completely understood. Here, our aim was to determine molecular changes that could unveil targetable mechanisms underlying this drug complication. We examined the expression and downstream activity of dopamine receptors (DR) in the striatum of 1-methyl-4-phenyl-1,2,3,6 tetrahydropiridine (MPTP)-lesioned monkeys with and without L-DOPA treatment. Four monkeys were made dyskinetic and other four received a shorter course of L-DOPA and did not develop LID. Our results show that L-DOPA treatment induces an increase in DRD2 and DRD3 expression in the postcommissural putamen, but only DRD3 is correlated with the severity of LID. Dyskinetic monkeys show a hyperactivation of the canonical DRD1-signaling pathway, measured by an increased phosphorylation of protein kinase A (PKA) and its substrates, particularly DARPP32. In contrast, activation of the DRD2-signaling pathway, visible in the levels of Akt phosphorylated on Thr308 and GSK3β on Ser9, is associated with L-DOPA treatment, independently of the presence of dyskinesias. Our data clearly demonstrate that dyskinetic monkeys present a dysregulation of the DRD3 receptor and the DRD1 pathway with a sustained increase of PKA activity in the postcommissural putamen. Importantly, we found that all signaling changes related to long-term L-DOPA administration are exquisitely restricted to the postcommissural putamen, which may be related to the recurrent failure of pharmacological approaches.

Opioid modulation of prolactin secretion induced by stress during late pregnancy. Role of ovarian steroids

BackgroundThe opioid system modulates prolactin release during late pregnancy. Its role and the participation of ovarian hormones in this modulation are explored in ether stress-induced prolactin release. Methods/ResultsEstrous, 3-day and 19-day pregnant rats were used. We administered the antagonist mifepristone (Mp) and tamoxifen to evaluate progesterone and estradiol action in naloxone (NAL, opioid antagonist) or saline treated rats. Ether stress had no effect on serum prolactin levels in controls but increased prolactin release in NAL-treated rats. Prolactin response to stress in NAL-treated rats was blocked by l-DOPA administration. Mp treatment on day 18 of pregnancy increased prolactin levels after stress without alterations by NAL. Tamoxifen on days 14 and 15 of pregnancy completely blocked Mp and NAL effects on prolactin release at late pregnancy. In contrast, stress significantly increased prolactin levels in estrous rats and pretreatment with NAL prevented this. On day 3 of pregnancy, at 6.00 p.m., stress and NAL treatment inhibited prolactin levels in saline-treated rat. No effect of stress or NAL administration was detected on day 3 of pregnancy at 9.00 a.m. icv administration of specific opioids antagonist, B-Funaltrexamine but not Nor-Binaltorphimine or Naltrindole, caused a significant increase in stress-induced prolactin release. ConclusionsOpioid system suppression of prolactin stress response during late pregnancy was observed only after progesterone withdrawal, involving a different opioid mechanism from its well-established stimulatory role. This mechanism acts through a mu opioid receptor and requires estrogen participation. The opioid system and progesterone may modulate stress-induced prolactin release, probably involving a putative prolactin-releasing factor.

Dopamine differently modulates central cholinergic circuits in patients with Alzheimer disease and CADASIL

Short-latency afferent inhibition (SAI) technique gives the opportunity to non-invasively test an inhibitory circuit in the human cerebral motor cortex that depends mainly on central cholinergic activity. Important SAI abnormalities have been reported in both patients with Alzheimer disease (AD) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a model of "pure" vascular dementia (VD). Interestingly, a normalization of SAI was observed in AD after levo-dopa (L-dopa) administration. We aimed to determine whether the pharmacological manipulation of the dopaminergic system can also interfere with SAI test in CADASIL patients, compared with AD patients and healthy controls. SAI was found to be significantly reduced in both patient groups. L-Dopa significantly increased SAI in the AD patients, while it failed to restore SAI abnormality in CADASIL patients. Therefore, L-dopa-mediated changes on SAI in AD patients seem to be a specific effect. The present study supports the notion that relationship between acetylcholine and dopamine systems may be specifically abnormal in AD. L-Dopa challenge may thus be able to differentiate the patients with AD or a mixed form of dementia from those with "pure" VD.

Preventive effect of rikkunshito on gastric motor function inhibited by l-dopa in rats

We previously reported that ghrelin prevented l-dopa (LD)-induced inhibition of gastric emptying (GE) of a non-nutrient solution in rats. Parkinson's disease treatment involves the combined administration of l-dopa with the enzyme l-amino acid decarboxylase inhibitor, carbidopa (CD) to reduce peripheral formation of dopamine. We investigated the effect LD/CD given orogastrically (og) on GE of a non-nutrient or nutrient meal and whether og pretreatment with rikkunshito, a kampo medicine clinically used to treat gastroparesis, influenced LD/CD effect on GE and postprandial antral and duodenal motility in conscious rats. LD/CD (20/2mgkg−1) decreased significantly GE to 26.3±6.0% compared to 61.2±3.2% in og vehicle monitored 20-min after a non-nutrient meal and to 41.9±5.8% compared to 72.9±5.2% in og vehicle monitored 60min after a nutrient meal. Rikkunshito (0.5 or 1.0gkg−1) reduced the LD/CD (20/2mgkg−1) inhibition of GE of non-nutrient meal (36.9±7.4% and 46.6±4.8% respectively vs. 12.1±7.4% in og vehicle plus LD/CD) while having no effect alone (56.6±8.5%). The ghrelin antagonist, [d-Lys3]-GHRP-6 (1mgkg−1) injected intraperitoneally partially reversed rikkunshito preventive effect on LD/CD-inhibited GE. Rikkunshito (1.0gkg−1) blocked LD/CD (20/2mgkg−1)-induced delayed GE of a nutrient meal and the reduction of postprandial antral motility. In 6-hydroxydopamine-induced Parkinson's disease rat model, rikkunshito (1.0gkg−1, og) also prevented LD/CD-inhibited gastric emptying of a nutrient meal and enhanced fasting plasma levels of acylated ghrelin. These data indicate that oral rikkunshito alleviates the delayed GE induced by LD/CD in naïve and PD rat model in part through ghrelin-related mechanisms.

Differential Dopamine Receptor Occupancy Underlies L-DOPA-Induced Dyskinesia in a Rat Model of Parkinson's Disease

Dyskinesia is a major side effect of an otherwise effective L-DOPA treatment in Parkinson's patients. The prevailing view for the underlying presynaptic mechanism of L-DOPA-induced dyskinesia (LID) suggests that surges in dopamine (DA) via uncontrolled release from serotonergic terminals results in abnormally high level of extracellular striatal dopamine. Here we used high-sensitivity online microdialysis and PET imaging techniques to directly investigate DA release properties from serotonergic terminals both in the parkinsonian striatum and after neuronal transplantation in 6-OHDA lesioned rats. Although L-DOPA administration resulted in a drift in extracellular DA levels, we found no evidence for abnormally high striatal DA release from serotonin neurons. The extracellular concentration of DA remained at or below levels detected in the intact striatum. Instead, our results showed that an inefficient release pool of DA associated with low D2 receptor binding remained unchanged. Taken together, these findings suggest that differential DA receptor activation rather than excessive release could be the underlying mechanism explaining LID seen in this model. Our data have important implications for development of drugs targeting the serotonergic system to reduce DA release to manage dyskinesia in patients with Parkinson's disease.

Oscillatory subthalamic nucleus activity is modulated by dopamine during emotional processing in Parkinson's disease

Dopaminergic denervation in Parkinson's disease (PD) leads to motor deficits but also depression, lack of motivation and apathy. These symptoms can be reversed by dopaminergic treatment, which may even lead to an increased hedonic tone in some patients with PD. Here, we tested the effects of dopamine on emotional processing as indexed by changes in local field potential (LFP) activity of the subthalamic nucleus (STN) in 28 PD patients undergoing deep brain stimulation. LFP activity from the STN was recorded after the administration of levodopa (ON group) or after overnight withdrawal of medication (OFF group) during presentation of an emotional picture-viewing task. Neutral and emotionally arousing pleasant and unpleasant stimuli were chosen from the International Affective Picture System. We found a double dissociation of the alpha band response depending on dopamine state and stimulus valence: dopamine enhanced the processing of pleasant stimuli, while activation during unpleasant stimuli was reduced, as indexed by the degree of desynchronization in the alpha frequency band. This pattern was reversed in the OFF state and more pronounced in the subgroup of non-depressed PD patients. Further, we found an early gamma band increase with unpleasant stimuli that occurred when ON but not OFF medication and was correlated with stimulus arousal. The late STN alpha band decrease is thought to represent active processing of sensory information. Our findings support the idea that dopamine enhances approach-related processes during late stimulus evaluation in PD. The early gamma band response may represent local encoding of increased attention, which varies as a function of stimulus arousal.

Molecular adaptations of striatal spiny projection neurons during levodopa-induced dyskinesia

Levodopa treatment is the major pharmacotherapy for Parkinson's disease. However, almost all patients receiving levodopa eventually develop debilitating involuntary movements (dyskinesia). Although it is known that striatal spiny projection neurons (SPNs) are involved in the genesis of this movement disorder, the molecular basis of dyskinesia is not understood. In this study, we identify distinct cell-type-specific gene-expression changes that occur in subclasses of SPNs upon induction of a parkinsonian lesion followed by chronic levodopa treatment. We identify several hundred genes, the expression of which is correlated with levodopa dose, many of which are under the control of activator protein-1 and ERK signaling. Despite homeostatic adaptations involving several signaling modulators, activator protein-1-dependent gene expression remains highly dysregulated in direct pathway SPNs upon chronic levodopa treatment. We also discuss which molecular pathways are most likely to dampen abnormal dopaminoceptive signaling in spiny projection neurons, hence providing potential targets for antidyskinetic treatments in Parkinson's disease.

Verificação dos efeitos da Levodopa na deglutição de pacientes com doença de Parkinson

Objetivo : Avaliar os efeitos da Levodopa na deglutição de pacientes com Doença de Parkinson (DP). Métodos : O estudo foi realizado no Programa Pró-Parkinson do Hospital das Clínicas da Universidade Federal de Pernambuco. Foram estudados 20 pacientes com DP idiopática e 12 sujeitos normais (grupo controle). A eletromiografia de superfície (EMGs) foi registrada sobre a musculatura supra-hióidea, durante a deglutição de 3 ml e 10 ml de água e iogurte. Cada volume foi repetido cinco vezes. Esse protocolo foi realizado no grupo com DP antes e após a medicação, período off e on, e no grupo controle, uma única vez. Resultados : A amplitude das EMGs foi significativamente maior nos sujeitos do grupo controle do que nos pacientes com DP (off), na deglutição de cada volume de água. A duração das EMGs foi significativamente maior na deglutição de 3 ml de água e iogurte em pacientes com DP (off). Durante a fase on, diferenças significativas não foram notadas. Conclusão : A administração de Levodopa em pacientes com DP parece influenciar a amplitude e duração da EMGs dos músculos supra-hióideos, aproximando as variáveis aos valores de normalidade.

The NK1 receptor antagonist N-acetyl-l-tryptophan reduces dyskinesia in a hemi-parkinsonian rodent model

BackgroundDyskinesia or abnormal involuntary movements (AIMs) are a disabling effect of chronic l-DOPA administration and consequent pulsatile stimulation of dopamine receptors. This abnormal activation causes maladaptive changes including upregulation of FosB expression in dynorphin containing striatal cells. Substance P (SP) is co-localized within dynorphin positive cells and is increased within the substantia nigra by l-DOPA (l-3,4-dihydroxyphenylalanine) treatment. Accordingly, we determined if treatment with a SP NK1 receptor antagonist reduced the onset of l-DOPA induced dyskinesia (LID) in the hemi-parkinsonian rodent model. MethodsAdult male Sprague–Dawley rats underwent unilateral 6-OHDA (6-hydroxydopamine-hydrobromide) lesions of the medial forebrain bundle. At day 21, daily administration commenced of either l-DOPA (6 mg/kg plus 15 mg/kg of benseraside), l-DOPA with the NK1 antagonist N-acetyl-l-tryptophan (NAT) or equal volume of saline. Animals were tested with the rodent AIM scale assessing axial, contralateral forelimb and orolingual AIMs. Assessment of l-DOPA induced turning was undertaken, and motor function determined using the accelerating rotarod and adjusting step test. Dopaminergic neuronal counts and immunoreactivity for SP and FosB were undertaken. ResultsAll animals treated with l-DOPA alone developed dyskinesia, whereas combined administration of NAT with l-DOPA significantly reduced onset of AIMs and prevented mild to moderate dyskinesia. In non-dyskinetic NAT treated animals, similar numbers of FosB+ striatal cells were recorded as in saline treated animals. Importantly NAT treatment did not interfere with the anti-parkinsonian effect of l-DOPA. ConclusionDaily administration of a SP NK1 receptor antagonist may represent a novel treatment regime that reduces the onset of LID whilst conserving motor function.

Molecular Effects of L-dopa Therapy in Parkinson’s Disease

Parkinson’s disease (PD) is one of the most common neurological diseases in elderly people. The mean age of onset is 55 years of age, and the risk for developing PD increases 5-fold by the age of 70. In PD, there is impairment in both motor and nonmotor (NMS) functions. The strategy of PD motor dysfunction treatment is simple and generally based on the enhancement of dopaminergic transmission by means of the L-dihydroxyphenylalanine (L-dopa) and dopamine (DA) agonists. L-dopa was discovered in the early -60's of the last century by Hornykiewicz and used for the treatment of patients with PD. L-dopa treatment in PD is related to decreased levels of the neurotransmitter (DA) in striatum and ab-sence of DA transporters on the nerve terminals in the brain. L-dopa may also indirectly stimulate the receptors of the D1 and D2 families. Administration of L-dopa to PD patients, especially long-time therapy, may cause side effects in the form of increased toxicity and inflammatory response, as well as disturbances in biothiols metabolism. Therefore, in PD pa-tients treated with L-dopa, monitoring of oxidative stress markers (8-oxo-2’-deoxyguanosine, apoptotic proteins) and in-flammatory factors (high-sensitivity C-reactive protein, soluble intracellular adhesion molecule), as well as biothiol com-pounds (homocysteine, cysteine, glutathione) is recommended. Administration of vitamins B6, B12, and folates along with an effective therapy with antioxidants and/or anti-inflammatory drugs at an early stage of PD might contribute to improvement in the quality of the life of patients with PD and to slowing down or stopping the progression of the disease.

Overexpression of the dopamine D3 receptor in the rat dorsal striatum induces dyskinetic behaviors

l-DOPA-induced dyskinesias (LID) are motor side effects associated with treatment of Parkinson's disease (PD). The etiology of LID is not clear; however, studies have shown that the dopamine D3 receptor is upregulated in the basal ganglia of mice, rats and non-human primate models of LID. It is not known if the upregulation of D3 receptor is a cause or result of LID. In this paper we tested the hypothesis that overexpression of the dopamine D3 receptor in dorsal striatum, in the absence of dopamine depletion, will elicit LID. Replication-deficient recombinant adeno-associated virus-2 expressing the D3 receptor or enhanced green fluorescent protein (EGFP) were stereotaxically injected, unilaterally, into the dorsal striatum of adult rats. Post-hoc immunohistochemical analysis revealed that ectopic expression of the D3 receptor was limited to neurons near the injection sites in the dorsal striatum. Following a 3-week recovery period, rats were administered saline, 6mg/kg l-DOPA, 0.1mg/kg PD128907 or 10mg/kg ES609, i.p., and motor behaviors scored. Rats overexpressing the D3 receptor specifically exhibited contralateral axial abnormal involuntary movements (AIMs) following administration of l-DOPA and PD128907 but not saline or the novel agonist ES609. Daily injection of 6mg/kg l-DOPA to the rats overexpressing the D3 receptor also caused increased vacuous chewing behavior. These results suggest that overexpression of the D3 receptor in the dorsal striatum results in the acute expression of agonist-induced axial AIMs and chronic l-DOPA-induced vacuous chewing behavior. Agonists such as ES609 might provide a novel therapeutic approach to treat dyskinesia.

Bradykinesia of posed smiling and voluntary movement of the lower face in Parkinson's disease

ObjectiveImpaired facial expression, including spontaneous and emotional movements such as smiling, has been often reported in Parkinson's disease (PD). There is a general consensus that spontaneous smiling is abnormal in PD. Investigations on posed smiling yield contrasting results. Moreover, no study has yet addressed the relationship between posed smiling and abnormalities of voluntary movements of the lower face, global motor impairment and the effects of dopaminergic medication. MethodsWe investigated the kinematics of posed smiling (mimicking a smile shown in a picture) and those of voluntary movements of the lower face (showing the teeth as fast as possible – voluntary grinning) in 15 patients with PD (ON and OFF therapy) and in 16 healthy controls. Facial movements were recorded using a 3D optoelectronic system and analyzed using dedicated software. ResultsSome kinematic parameters of both posed smiling and voluntary grinning were abnormally lower in PD patients in comparison to healthy subjects. The kinematics of posed smiling correlated with those of voluntary grinning in PD patients but not in healthy controls. Posed smiling and voluntary grinning abnormalities were related to global motor severity but did not significantly improve upon L-dopa administration. ConclusionsThese results suggest that posed smiling and voluntary grinning are both abnormal in PD patients and that they are likely mediated by a common pathophysiological mechanism.

Effects of l-DOPA pre-loading on the uptake of boronophenylalanine using the F98 glioma and B16 melanoma models

The present study was undertaken to evaluate the effects of l-DOPA pre-loading on the uptake of BPA using the F98 rat glioma and the murine B16 melanoma models. In vitro pretreatments of F98 glioma and B16 melanoma cells with l-DOPA, followed by exposure to BPA increased boron uptake, as determined by inductively coupled plasma-optical emission spectroscopy (ICP-OES). Based on this, in vivo studies were initiated in F98 glioma bearing rats. Initially, the l-DOPA dosing paradigm was evaluated. Maximum tumor boron uptake was observed following i.p. administration of l-DOPA (50mg/kg) followed 24h later by BPA (31.8±8.9 vs. 17.2±6.3µg/g for BPA alone). Next, the effect of l-DOPA pre-loading as a function of the route of administration of BPA was evaluated in F98 glioma bearing rats. The greatest increase in uptake was seen following i.v. administration of BPA, while in contrast no significant increase was seen following intracarotid (i.c.) administration (38.6±12.4 vs. 34.2±10.9). Cellular localization of the F98 glioma, as determined by secondary ion mass spectrometry (SIMS) boron imaging revealed equivalent tumor boron concentrations following l-DOPA pre-loading. In vivo studies in B16 melanoma bearing mice showed equivalent tumor boron values in treated and untreated mice, suggesting that the effects of l-DOPA pre-loading may depend both on the histologic type of tumor and its anatomic site.

Levodopa-related cysteinyl–glycine and cysteine reduction with and without catechol-O-methyltransferase inhibition in Parkinson’s disease patients

Oxidative stress is influenced by the thiol homeostasis, which regulates the redox milieu via glutathione. Components of glutathione metabolism are cysteine and cysteinyl-glycine. Both substrates decay following levodopa application or dopamine-related oxidative stress. Objective was to investigate the impact of an acute levodopa application with and without catechol-O-methyltransferase inhibitor on cysteine- and cysteinyl-glycine plasma levels. On two investigation days, 13 patients with Parkinson's disease took one retarded release 200-mg levodopa/50mg carbidopa-containing tablet or one 150-mg levodopa/50-mg carbidopa/200-mg entacapone formulation under standardized conditions. Levodopa, 3-O-methyldopa, cysteine and cysteinyl-glycine were measured at baseline, 80 and 140min following levodopa administration. Cysteine and cysteinyl-glycine similarly decreased, levodopa was nearly equal during both conditions. Entacapone lowered 3-O-methyldopa. Cysteine decay may be due to an elevated glutathione generation, which consumes cysteine. Cysteinyl-glycine decrease results from the alternative glutathione transformation to its oxidized form glutathione dissulfide after free radical scavenging.

L-dopa reverses behavioral deficits in the Pitx3 mouse fetus.

Studies of fetal rodents have provided evidence that early emerging behaviors, such as the suckling response, are dependent on the developing dopaminergic system. Although connections have been made between manipulations of dopamine and altered behavioral responses, the specific neural pathways involved have yet to be discovered. In this study, we examined the neurobehavioral output of the nigrostriatal pathway, using the Pitx3ak/2J mouse model (Pitx3). Used extensively in the study of Parkinson's disease, the Pitx3 mouse has very specific prenatal loss of dopaminergic neurons solely in the nigrostriatal pathway. Because of this specificity, we hypothesized that behavioral deficits specific to the nigrostriatal pathway would be reversed with administration of the dopamine precursor 3,4-dihydroxyphenylalanine (L-dopa). To test this hypothesis, homozygous mutant and heterozygous control fetal subjects were administered 1 of 4 doses (0, 25, 50, or 75 mg/kg) of L-dopa on the day before birth. Quantification of fetal behavior was scored from video recordings of behavioral observations. The behavioral measures used were (a) spontaneous movement activity; (b) state organization, from quantifications of high- and low-amplitude movements; (c) interlimb movement synchrony, a measure of limb coordination; and (d) oral grasp, similar to a newborn infant suckling response. Specific behavioral deficits observed in the Pitx3 mutants were reversed by L-dopa administration in a dose-dependent manner. However, different deficits required dissimilar doses for reversal, suggesting that some early emerging behaviors may be more sensitive to the administration of L-dopa. Taken together, this study provides valuable information about prenatal behaviors dependent on the nigrostriatal pathway.