Effects Of Levodopa Research Articles

ONO-2506 Can Delay Levodopa-induced Dyskinesia in the Early Stage

Background: Levodopa-induced dyskinesia (LID) is a common motor complication of levodopa (L-DOPA) treatment for Parkinson's disease (PD). In recent years, the role of astrocytes in LID has increasingly attracted attention. Objective: To explore the effect of an astrocyte regulator (ONO-2506) on LID in a rat model and the potential underlying physiological mechanism. Methods: Unilateral LID rat models, established by administering 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle through stereotactic injection, were injected with ONO-2506 or saline into the striatum through brain catheterization and were administered L-DOPA to induce LID. Through a series of behavioral experiments, LID performance was observed. Relevant indicators were assessed through biochemical experiments. Results: In the LID model of 6-OHDA rats, ONO-2506 significantly delayed the development and reduced the degree of abnormal involuntary movement in the early stage of L-DOPA treatment and increased glial fibrillary acidic protein and glutamate transporter 1 (GLT-1) expression in the striatum compared to saline. However, there was no significant difference in the improvement in motor function between the ONO-2506 and saline groups. Conclusions: ONO-2506 delays the emergence of L-DOPA-induced abnormal involuntary movements in the early stage of L-DOPA administration, without affecting the anti-PD effect of L-DOPA. The delaying effect of ONO-2506 on LID may be linked to the increased expression of GLT-1 in the rat striatum. Interventions targeting astrocytes and glutamate transporters are potential therapeutic strategies to delay the development of LID.

Long-term levodopa ameliorates sequence effect in simple, but not complex walking in early Parkinson's disease patients

BackgroundThe sequence effect (SE) is characterized by the progressive decrement of movements and is often observed in Parkinson's disease (PD) patients. While acute effect of levodopa does not ameliorate the SE, the effect of long-term levodopa treatment for the SE remains unknown. ObjectiveWe aimed to elucidate the SEs during various gait conditions and their response to long-term levodopa treatment in drug-naïve PD patients. MethodsNineteen drug-naïve PD patients and 21 healthy controls were enrolled. Gait parameters were measured via wearable inertial sensors in the following conditions:1) straight walking, 2) circular walking: walking a circle of 1 m diameter in a clock-wise direction for 3 laps, 3) straight or circular walking under cognitive-motor dual-task (serial 7s subtractions). PD patients were evaluated at baseline, within 1 h after intravenous administration of levodopa, and after one, three, and six months treatment with levodopa. The SE was measured by a linear regression slope by plotting consecutive stride lengths over steps. Patients were also separately analyzed depending on laterality of symptoms. ResultsLong-term levodopa treatment ameliorated the SE only during single-task straight walking. The SE during circular walking was exacerbated after long-term levodopa treatment for right-side dominant patients. During dual-task straight walking, the SE at baseline was greater in right-side dominant PD patients. ConclusionsThe SE only during single-task straight walking can be ameliorated by long-term levodopa treatment. However, the SE may be exaggerated by cognitive motor interference or by asymmetrical stride length with/without long-term levodopa treatment, depending on the laterality of symptoms.

Effects of levodopa on gut bacterial antibiotic resistance in Parkinson's disease rat.

The second most prevalent neurodegenerative ailment, Parkinson's disease (PD), is characterized by both motor and non-motor symptoms. Levodopa is the backbone of treatment for PD at the moment. However, levodopa-induced side effects, such as dyskinesia, are commonly seen in PD patients. Recently, several antibiotics were found to present neuroprotective properties against neurodegenerative and neuro-inflammatory processes, which might be developed to effective therapies against PD. In this study, we aimed to identify if levodopa treatment could influence the gut bacterial antibiotic resistance in PD rat. Fecal samples were collected from healthy rats and 6-OHDA induced PD rats treated with different doses of levodopa, metagenomic sequencing data showed that levodopa resulted in gut bacteria composition change, the biomarkers of gut bacteria analyzed by LEfSe changed as well. More interestingly, compared with levodopa (5 mg/kg)-treated or no levodopa-treated PD rats, levodopa (10 mg/kg) caused a significant decrease in the abundance of tetW and vanTG genes in intestinal bacteria, which were related to tetracycline and vancomycin resistance, while the abundance of AAC6-lb-Suzhou gene increased apparently, which was related to aminoglycosides resistance, even though the total quantity of Antibiotic Resistance Gene (ARG) and Antibiotic Resistance Ontology (ARO) among all groups did not significantly differ. Consequently, our results imply that the combination of levodopa and antibiotics, such as tetracycline and vancomycin, in the treatment of PD may decrease the amount of corresponding antibiotic resistance genes in gut bacteria, which would give a theoretical basis for treating PD with levodopa combined with tetracycline and vancomycin in the future.

Mechanism of circular RNA-mediated regulation of L-DOPA to improve wet age-related macular degeneration

This study aimed to investigate the effect and mechanism of levodopa (L-DOPA) in the treatment of age-related macular degeneration (AMD). A wet AMD cell model was created via CoCl2 treatment of ARPE-19 cells. The cytoprotective effects of L-DOPA in the model were determined using CCK-8, flow cytometry, TUNEL, qPCR, and ELISA assays. Subsequently, circRNA sequencing and bioinformatics analysis were used to screen differentially expressed circRNAs, which were overexpressed in ARPE-19 cells, to explore their role in wet AMD. The findings revealed that 200 μM CoCl2 treatment inhibited the cell viability and the production of tyrosinase, melanin, and pigment epithelium-derived growth factor but promoted apoptosis and the expression of vascular endothelial growth factor in ARPE-19 cells. Moreover, 20 μM L-DOPA exerted the best therapeutic effect on the model. qPCR showed that Hsa_circ_0018401 (circ-SGMS1) was significantly differentially expressed in each experimental group, which was consistent with the sequencing results. The overexpression of circ-SGMS1 in ARPE-19 cells reversed the effects of CoCl2. Fluorescence in situ hybridization showed that circ-SGMS1 was expressed more in the nucleus than in the cytoplasm. qPCR assays indicated that circ-SGMS1 overexpression did not have a significant effect on the expressions of VEGFA and KDR but significantly reduced the expressions of HIF-1a and THBS1. Circ-SGMS1 is of immense significance in the AMD treatment mechanism of L-DOPA. Overexpression of circ-SGMS1 may alleviate wet AMD by inhibiting HIF-1a and THBS1 expression.

Anti-inflammatory effects of dopamine on microglia and a D1 receptor agonist ameliorates neuroinflammation of the brain in a rat delirium model.

Microglia play a central role in neuroinflammatory processes by releasing proinflammatory mediators. This process is tightly regulated along with neuronal activities, and neurotransmitters may link neuronal activities to the microglia. In this study, we showed that primary cultured rat microglia express the dopamine (DA) D1 receptor (D1R) and D4R, but not D2R, D3R, or D5R. In response to a D1R-specific agonist SKF-81297 (SKF), the cultured microglia exhibited increased intracellular cAMP levels. DA and SKF suppressed lipopolysaccharide (LPS)-induced expression of interleukin-1β (IL-1β) and tumor necrosis α (TNFα) in cultured microglia. Microglia in the normal mature rat prefrontal cortex (PFC) were sorted and significant expression of D1R, D2R, and D4R was observed. A delirium model was established by administering LPS intraperitoneally to mature male Wistar rats. The model also displayed sleep-wake disturbances as revealed by electroencephalogram and electromyogram recordings as well as increased expression of IL-1β and TNFα in the PFC. DA levels were increased in the PFC 21h after LPS administration. Increased cytokine expression was observed in sorted microglia from the PFC of the delirium model; however, TNFα, but not IL-1β expression, was abruptly decreased 21h after LPS administration in the delirium model, whereas DA levels were increased. A D1R antagonist SCH23390 partially abolished the TNFα expression change. This suggests that endogenous DA may play a role in suppressing neuroinflammation. Administration of the DA precursor L-DOPA or SKF to the delirium model rats inhibited the expression of IL-1β and TNFα. The simultaneous administration of clozapine, a D4R antagonist, strengthened the suppressive effects of L-DOPA. These results suggest that D1R mediates the suppressive effects of LPS-induced neuroinflammation, in which microglia may play an important role. Agonists for D1R may be effective for treating delirium.

Effects of Oral Levodopa on Balance in People with Idiopathic Parkinson's Disease.

Balance impairment is a frequent cause of morbidity and mortality in people with Parkinson's disease (PD). As opposed to the effects of appendicular motor symptoms, the effects of Levodopa on balance impairment in idiopathic PD are less clear. To review the literature on the effects of oral Levodopa on clinical balance test performance, posturography, step initiation, and responses to perturbation in people with idiopathic PD (PwPD). A systematic search of three scientific databases (Pubmed, Embase, and Web of Science) was conducted in accordance with PRISMA guidelines. For the pilot meta-analysis, standardized mean differences with 95% confidence intervals were calculated using an inverse variance random effects model. Data not suitable for implementation in the meta-analysis (missing means or standard deviations, and non-independent outcomes) were analyzed narratively. A total of 2772 unique studies were retrieved, of which 18 met the eligibility criteria and were analyzed, including data of 710 idiopathic PwPD. Levodopa had a significant positive effect on the Berg Balance Scale, the Push and Release test, and jerk and frequency parameters during posturography. In contrast, some significant negative effects on velocity-based sway parameters were found during posturography and step initiation. However, Levodopa had no significant effect on most step initiation- and all perturbation parameters. The effects of Levodopa on balance in PwPD vary depending on the outcome parameters and patient inclusion criteria. A systematic approach with well-defined outcome parameters, and prespecified, sensitive and reliable tests is needed in future studies to unravel the effects of oral Levodopa on balance.

The use of the drug L-Carnitine Rompharm in patients with Parkinson's disease in the context of rational pharmacotherapy

The basic drug therapy for Parkinson's disease (PD) includes levodopa, dopamine receptor agonists (ADRs), type B monoamine oxidase enzyme inhibitors, catechol-O-methyltransferase inhibitors, and amantadine. In recent years, the efficacy of L-carnitine in neurodegenerative diseases and depression, which is often associated with PD, has been reported.
 Aim. To study the efficacy and safety of levocarnitine (L-Carnitine Rompharm) in PD patients of different ages and disease histories combined with ADR and levodopa.
 Materials and methods. A total of 142 patients with PD (aged 43 to 82 years) were followed-up from February 2020 to July 2022. All of these patients underwent clinical-neurological and neuropsychological examinations. In all patients, L-Carnitine Rompharm was used in the complex therapy of PD in combination with ADR and levodopa. Therapy efficacy was assessed using the International Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS).
 Results. After the course of therapy, significant (p0.05) improvements in non-motor manifestations of PD (MDS UPDRS scale I), motor manifestations of PD (MDS UPDRS scale II), and motor function indices (MDS UPDRS scale III) were observed in all age groups. Improvements in hypokinesia, rigidity, motor fluctuations (depletion of levodopa effect), peak dose dyskinesia, and postural instability were observed; thought processes, behavior, mood, and daily life activity were also improved. L-carnitine showed good tolerability and absence of side effects.
 Conclusion. The efficacy and safety of L-Carnitine Rompharm in PD patients of different ages have been demonstrated.

Multimodal imaging study of the 5-HT1A receptor biased agonist, NLX-112, in a model of L-DOPA-induced dyskinesia

IntroductionThe leading treatment for motor signs of Parkinson's disease is L-DOPA, but, upon extended use, it can lead to levodopa-induced dyskinesia (LID). Serotonergic neurons are involved in LID etiology and previous pre-clinical studies have shown that NLX-112, a 5-HT1A biased agonist, has robust antidyskinetic effects. Here, we investigated its effects in hemiparkinsonian (HPK) rats with a unilateral nigrostriatal 6-OHDA lesion. MethodsWe compared HPK rats with LID (i.e., sensitized to the dyskinetic effects of chronic L-DOPA) and without LID (HPK-non-LID), using [18F]FDG PET imaging and fMRI functional connectivity following systemic treatment with saline, L-DOPA, NLX-112 or L-DOPA + NLX-112. ResultsIn HPK-non-LID rats, [18F]FDG PET experiments showed that L-DOPA led to hypermetabolism in motor areas (cerebellum, brainstem, and mesencephalic locomotor region) and to hypometabolism in cortical regions. L-DOPA effects were also observed in HPK-LID rats, with the additional emergence of hypermetabolism in raphe nuclei and hypometabolism in hippocampus and striatum. NLX-112 attenuated L-DOPA-induced raphe hypermetabolism and cingulate cortex hypometabolism in HPK-LID rats. Moreover, in fMRI experiments NLX-112 partially corrected the altered neural circuit connectivity profile in HPK-LID rats, through activity in regions rich in 5-HT1A receptors. ConclusionThis neuroimaging study sheds light for the first time on the brain activation patterns of HPK-LID rats. The 5-HT1A receptor agonist, NLX-112, prevents occurrence of LID, likely by activating pre-synaptic autoreceptors in the raphe nuclei, resulting in a partial restoration of brain metabolic and connectivity profiles. In addition, NLX-112 also rescues L-DOPA-induced deficits in cortical activation, suggesting potential benefit against non-motor symptoms of Parkinson’s disease.

NMDA receptor–related mechanisms of dopaminergic modulation of tDCS-induced neuroplasticity

Abstract Background: Dopamine is a key neuromodulator of neuroplasticity, and an important neuronal substrate of learning, and memory formation, which critically involves glutamatergic N-Methyl-D-aspartate (NMDA) receptors. Dopamine modulates NMDA receptor activity via dopamine D1 and D2 receptor subtypes. It is hypothesized that dopamine focuses long term potentiation (LTP)-like plasticity, i.e. reduces diffuse widespread but enhances locally restricted plasticity via a D2 receptor-dependent NMDA receptor activity reduction. Here, we explored NMDA receptor-dependent mechanisms underlying DAergic modulation of LTP-like plasticity induced by transcranial direct current stimulation (tDCS). Methods: Eleven healthy, right-handed volunteers received anodal tDCS (1 mA, 13 min) over the left motor cortex combined with DAergic agents (the D2 receptor agonist bromocriptine, levodopa (L-Dopa) for general dopamine enhancement, or placebo), and the partial NMDA receptor agonist D-cycloserine (CYC; dosages of 50, 100 and 200 mg, or placebo). Cortical excitability was monitored by transcranial magnetic stimulation-induced motor-evoked potentials. Results: Low-dose CYC alone did not relevantly change anodal tDCS-generated LTP-like plasticity, while medium dosage prolonged and high dosage CYC diminished aftereffects of stimulation. L-Dopa or bromocriptine alone reversed or abolished anodal tDCS-induced excitatory plasticity respectively, which was re-established by medium-dose CYC. Adding low dosage CYC did not alter the effects of bromocriptine and L-Dopa, while high-dose CYC abolished the after-effects. Conclusions: Our results suggest that the focusing effect of dopamine on LTP-like plasticity is caused by D2 receptor-generated reduction of NMDA receptor activity. Medium-dose CYC, as compared to low and high dosages, restored anodal tDCS-induced after-effects possibly due to optimizing calcium influx via enhancement of NMDA receptor activity Research Category and Technology and Methods Basic Research: 9. Transcranial Direct Current Stimulation (tDCS) Keywords: transcranial direct current stimulation, dopamine, NMDA receptor, plasticity

Improved natural melanin production by Aspergillus nidulans after optimization of factors involved in the pigment biosynthesis pathway

BackgroundMelanin is a natural pigment that can be applied in different fields such as medicine, environment, pharmaceutical, and nanotechnology. Studies carried out previously showed that the melanin produced by the mel1 mutant from Aspergillus nidulans exhibits antioxidant, anti-inflammatory, and antimicrobial activities, without any cytotoxic or mutagenic effect. These results taken together suggest the potential application of melanin from A. nidulans in the pharmaceutical industry. In this context, this study aimed to evaluate the effect of factors L-tyrosine, glucose, glutamic acid, l-DOPA, and copper on melanin production by the mel1 mutant and to establish the optimal concentration of these factors to maximize melanin production.ResultsThe results showed that l-DOPA, glucose, and copper sulfate significantly affected melanin production, where l-DOPA was the only factor that exerted a positive effect on melanin yield. Besides, the tyrosinase activity was higher in the presence of l-DOPA, considered a substrate required for enzyme activation, this would explain the increased production of melanin in this condition. After establishing the optimal concentrations of the analyzed factors, the melanin synthesis was increased by 640% compared to the previous studies.ConclusionsThis study contributed to elucidating the mechanisms involved in melanin synthesis in A. nidulans as well as to determining the optimal composition of the culture medium for greater melanin production that will make it possible to scale the process for a future biotechnological application.

Pharmacological Mechanism of the Non-hallucinogenic 5-HT2A Agonist Ariadne and Analogs.

Ariadne is a non-hallucinogenic analog in the phenylalkylamine chemical class of psychedelics that is closely related to an established synthetic hallucinogen, 2,5-dimethoxy-4-methyl-amphetamine (DOM), differing only by one methylene group in the α-position to the amine. Ariadne has been tested in humans including clinical trials at Bristol-Myers Company that indicate a lack of hallucinogenic effects and remarkable therapeutic effects, such as rapid remission of psychotic symptoms in schizophrenics, relaxation in catatonics, complete remission of symptoms in Parkinson's disease (PD), and improved cognition in geriatric subjects. Despite these provocative clinical results, the compound has been abandoned as a drug candidate and its molecular pharmacology remained unknown. Here, we report a detailed examination of the in vitro and in vivo pharmacology of Ariadne and its analogs, and propose a molecular hypothesis for the lack of hallucinogenic effects and the therapeutic potential of this compound class. We also provide a summary of previous clinical and preclinical results to contextualize the molecular signaling data. Our results show that Ariadne is a serotonin 5-HT2 receptor agonist, exhibits modest selectivity over 5-HT1 receptors, has no relevant activity at 5-HT4,5,7 and other aminergic receptors, and no substantial affinity at plasma membrane monoamine transporters. Compared to DOM, Ariadne shows lower signaling potency and efficacy in multiple signaling pathways examined (Gq, G11, and β-arrestin2) coupled to 5-HT2A receptors. We confirmed the shift in signaling for an α-propyl analog and provide a molecular docking rationale for the progressive decrease in signaling potency with the growing length of the α-substituent. Ariadne versus DOM exhibits no apparent change in the relative preference between Gq/11 activation and β-arrestin2 recruitment; instead, there is a small but consistent drop in efficacy in these signaling channels. Ariadne acts as a 5-HT2A agonist in vivo in mice and shows markedly attenuated head twitch response (HTR) in comparison to its hallucinogenic analogs, consistent with previous studies in rabbits, cats, and dogs. Hence, we propose the lower 5-HT2A receptor signaling efficacy of this compound class as an explanatory model for the lack of hallucinogenic effects of Ariadne in humans and the dramatically attenuated hallucinosis-like effects in animals (5-HT2A signaling efficacy hypothesis). In terms of reverse translation of the noted clinical therapeutic effects, we used an auxilin knockout model of Parkinson's disease where Ariadne rescued severe motor deficits in this mouse line, on par with the effects of l-DOPA, a notable finding considering Ariadne's lack of activity at dopamine receptors and transporters. Ariadne emerges as a prototype of a new drug class, non-hallucinogenic 5-HT2A agonists, with considerable therapeutic potential across psychiatric and neurological indications.

Effects of Contralateral Deep Brain Stimulation and Levodopa on Subthalamic Nucleus Oscillatory Activity and Phase-Amplitude Coupling

BackgroundThe modulatory effects of medication and deep brain stimulation (DBS) on subthalamic nucleus (STN) neural activity in Parkinson's disease have been widely studied. However, effects on the contralateral side to the stimulated STN, in particular, changes in local field potential (LFP) oscillatory activity and phase-amplitude coupling (PAC), have not yet been reported. ObjectiveThe aim of this study was to examine changes in STN LFP activity across a range of frequency bands and STN PAC for different combinations of DBS and medication on/off on the side contralateral to the applied stimulation. Materials and MethodsWe examined STN LFPs that were recorded using externalized leads from eight parkinsonian patients during unilateral DBS from the side contralateral to the stimulation. LFP spectral power in alpha (5 to ∼13 Hz), low beta (13 to ∼20 Hz), high beta (20–30 Hz), and high gamma plus high-frequency oscillation (high gamma+HFO) (100–400 Hz) bands were estimated for different combinations of medication and unilateral stimulation (off/on). PAC between beta and high gamma+HFO in the STN LFPs was also investigated. The effect of the condition was examined using linear mixed models. ResultsPAC in the STN LFP was reduced by DBS when compared to the baseline condition (no medication and stimulation). Medication had no significant effect on PAC. Alpha power decreased with DBS, both alone and when combined with medication. Beta power decreased with DBS, medication, and DBS and medication combined. High gamma+HFO power increased during the application of contralateral DBS and was unaltered by medication. ConclusionsThe results provide new insights into the effects of DBS and levodopa on STN LFP PAC and oscillatory activity on the side contralateral to stimulation. These may have important implications in understanding mechanisms underlying motor improvements with DBS, including changes on both contralateral and ipsilateral sides, while suggesting a possible role for contralateral sensing during unilateral DBS.

Pulmonary function and medication effect in mild-stage subjects with Parkinson's disease.

Parkinson's disease (PD) causes a series of movement disorders, many of them starting in the early stage. To analyze the pulmonary function of mild-stage subjects with PD and to investigate the effects of levodopa on it. We included 21 patients with idiopathic PD and 20 healthy control subjects. The participants were submitted to spirometry and impulse oscillometry assessments. The PD patients were evaluated during the "off" and "on" phases of their anti-PD medication, which was was converted to levodopa in an equivalent daily dose. A statistical analysis was performed with cross-sectional (PD patients "off" medication versus controls) and paired (PD patients "off" medication versus PD patients "on" medication) tests. The effect of levodopa was calculated with partial Eta-squared (η2 ρ). Significance was set at 5%. The PD patients presented normal values in the impulse oscillometry. Regarding spirometry, the results indicated an incipient obstructive ventilatory disorder in the PD group - confirmed by patients' flow-volume curves. The PD patients received a daily dose of 354.7 ± 148.2 mg of levodopa. The paired analyses showed a small effect of anti-PD medication on pulmonary parameters (η2 ρ = 0.197 for spirometry and η2 ρ= 0.043 for impulse oscillometry). Patients with PD in the mild stage of the disease present pulmonary compliance and resistance compatible with normal parameters. The differences regarding the spirometric results indicate an incipient obstructive ventilatory disorder in patients with PD. Levodopa had small effect on pulmonary function in the mild stage of the disease.

Exploring the effects of dopamine on sensorimotor inhibition and mobility in older adults.

Dopaminergic activity decreases in older adults (OAs) with normal aging and is further reduced in Parkinson's disease (PD), affecting cortical motor and sensorimotor pathways. Levodopa is the prevailing therapy to counter dopamine loss in PD, though not all PD motor signs improve with levodopa. The purpose of this preliminary study was to explore the effects of levodopa on sensorimotor inhibition, gait and quiet standing in OAs and to investigate the relationships between sensorimotor inhibition and both gait and standing balance both OFF- and ON-levodopa. Fifteen OA males completed a gait, balance and sensorimotor assessments before and 1 h after they were given a 100mg dose of levodopa. Short-latency afferent inhibition quantified sensorimotor inhibition. Wearable sensors characterized gait (two-minute walk) and standing balance (1-min stance). No sensorimotor inhibition, gait, or standing balance measures changed from OFF- to ON-levodopa. When OFF-levodopa, worse inhibition significantly related to increased double stance (r = 0.62; p = 0.01), increased jerkiness of sway (r = 0.57; p = 0.03) and sway area (r = 0.58; p = 0.02). While ON-levodopa, worse inhibition related to increased arm swing range of motion (r = 0.63; p = 0.01) and jerkiness of sway (r = 0.53; p = 0.04). The relationship between SAI and arm swing excursion significantly changed from OFF- to ON-levodopa (z = - 3.05; p = 0.002; 95% confidence interval = - 0.95, - 0.21). Sensorimotor inhibition relationships to both gait and balance may be affected by dopamine in OAs. Cortical restructuring due to the loss of dopamine may be responsible for the heterogeneity of levodopa effect in people with PD and OAs.

Levodopa alters resting-state functional connectivity more selectively in Parkinson's disease with freezing of gait.

Freezing of gait (FOG) is a debilitating motor symptom of Parkinson's disease (PD). Although PD dopaminergic medication (L-DOPA) seems to generally reduce FOG severity, its effect on neural mechanisms of FOG remains to be determined. The purpose of this study was to quantify the effect of L-DOPA on brain resting-state functional connectivity in individuals with FOG. Functional magnetic resonance imaging was acquired at rest in 30 individuals living with PD (15 freezers) in the ON- and OFF- medication state. A seed-to-voxel analysis was performed with seeds in the bilateral basal ganglia nuclei, the thalamus and the mesencephalic locomotor region. In freezers, medication-state contrasts revealed numerous changes in resting-state functional connectivity, not modulated by L-DOPA in non-freezers. In freezers, L-DOPA increased the functional connectivity between the seeds and regions including the posterior parietal, the posterior cingulate, the motor and the medial prefrontal cortices. Comparisons with non-freezers revealed that L-DOPA generally normalizes brain functional connectivity to non-freezers levels but can also increase functional connectivity, possibly compensating for dysfunctional networks in freezers. Our findings suggest that L-DOPA could contribute to a better sensorimotor, attentional, response inhibition and limbic processing to prevent FOG when triggers are encountered but could also contribute to FOG by interfering with the processing capacity of the striatum. This study shows that levodopa taken to control PD symptoms induces changes in functional connectivity at rest, in freezers only. Increases (green) in functional connectivity of GPe, GPi, putamen and thalamus with cognitive, sensorimotor and limbic cortical regions of the Interference model (blue) was observed. Our results suggest that levodopa can normalize connections similar to non-freezers or increases connectivity to compensate for dysfunctional networks.

Dopamine increases risky choice while D2 blockade shortens decision time

Dopamine is crucially involved in decision-making and overstimulation within dopaminergic pathways can lead to impulsive behaviour, including a desire to take risks and reduced deliberation before acting. These behavioural changes are side effects of treatment with dopaminergic drugs in Parkinson disease, but their likelihood of occurrence is difficult to predict and may be influenced by the individual’s baseline endogenous dopamine state, and indeed correlate with sensation-seeking personality traits. We here collected data on a standard gambling task in healthy volunteers given either placebo, 2.5 mg of the dopamine antagonist haloperidol or 100/25 mg of the dopamine precursor levodopa in a within-subject design. We found an increase in risky choices on levodopa. Choices were, however, made faster on haloperidol with no effect of levodopa on deliberation time. Shortened deliberation times on haloperidol occurred in low sensation-seekers only, suggesting a correlation between sensation-seeking personality trait and baseline dopamine levels. We hypothesise that levodopa increases risk-taking behaviour via overstimulation at both D1 and D2 receptor level, while a single low dose of haloperidol, as previously reported (Frank and O’Reilly 2006), may block D2 receptors pre- and post-synaptically and may paradoxically lead to higher striatal dopamine acting on remaining striatal D1 receptors, causing speedier decision without influencing risk tolerance. These effects could also fit with a recently proposed computational model of the basal ganglia (Moeller and Bogacz 2019; Moeller et al. 2021). Furthermore, our data suggest that the actual dopaminergic drug effect may be dependent on the individual’s baseline dopamine state, which may influence our therapeutic decision as clinicians in the future.

A Pilot Trial of Dopamine Replacement for Dynamic Facial Expressions in Parkinson's Disease.

Current conflict exists regarding the potential beneficial effects of dopamine medications on facial expressivity in Parkinson's disease. Via digital video analysis software, we previously found reduced facial movement (entropy) and slower time to reach peak entropy in individuals with Parkinson's disease compared to controls. We aimed to determine whether levodopa medications improved parameters of dynamic facial expressions (amplitude, speed). A total of 34 individuals with idiopathic Parkinson's disease were videotaped making voluntary facial expressions (happy, fear, anger, disgust) when "on" and "off" levodopa. Participants were 52 to 80 years old, early to mid-stage disease, non-demented, and included more men (65%). Expressions were digitized and analyzed using software that extracted three variables: two indices of movement change (total entropy, percent entropy change) and time to reach peak expression. Indices of facial movement (total entropy, peak entropy) and timing were significantly improved when patients were "on" vs "off" medication (all F's ≥ 3.00, P < 0.05). For total movement and time to reach peak entropy, levodopa-related improvements were emotion nonspecific. Levodopa-related improvement for peak entropy was driven primarily by happy expressions. There was no relationship between quantitative indices and clinical measures of mood (depression, anxiety) and motor disease severity. The effects of levodopa on Parkinson's disease voluntary facial movement and on timing were robust and consistent with those of levodopa on other intentional movements in Parkinson's disease. This improvement possibly occurred because of levodopa enhanced activation of face representation areas in fronto-cortical regions or because of less movement-based suppression.

Effects of a New Natural Catechol-O-methyl Transferase Inhibitor on Two In Vivo Models of Parkinson's Disease.

A tetrahydroisoquinoline identified in Mucuna pruriens ((1R,3S)-6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-1,3-dicarboxylic acid, compound 4) was synthesized and assessed for its in vitro pharmacological profile and in vivo effects in two animal models of Parkinson's disease. Compound 4 inhibits catechol-O-methyltransferase (COMT) with no affinity for the dopaminergic receptors or the dopamine transporter. It restores dopamine-mediated motor behavior when it is co-administered with L-DOPA to C. elegans worms with 1-methyl-4-phenylpyridinium-damaged dopaminergic neurons. In a 6-hydroxydopamine rat model of Parkinson's disease, its co-administration at 30 mg/kg with L-DOPA enhances the effect of L-DOPA with an intensity similar to that of tolcapone 1 at 30 mg/kg but for a shorter duration. The effect is not dose-dependent. Compound 4 seems not to cross the blood-brain barrier and thus acts as a peripheral COMT inhibitor. COMT inhibition by compound 4 further validates the traditional use of M. pruriens for the treatment of Parkinson's disease, and compound 4 can thus be considered as a promising drug candidate for the development of safe, peripheral COMT inhibitors.

Effect of Levodopa and Environmental Setting on Gait and Turning Digital Markers Related to Falls in People with Parkinson's Disease.

It is unknown whether medication status (off and on levodopa) or laboratory versus home settings plays a role in discriminating fallers and non-fallers in people with Parkinson's disease (PD). To investigate which specific digital gait and turning measures, obtained with body-worn sensors, best discriminated fallers from non-fallers with PD in the clinic and during daily life. We recruited 34 subjects with PD (17 fallers and 17 non-fallers based on the past 6 month's falls). Subjects wore three inertial sensors attached to both feet and the lumbar region in the laboratory for a 3-minute walking task (both off and on levodopa) and during daily life activities for a week. We derived 24 digital (18 gait and 6 turn) measures from the 3-minute walk and from daily life. In clinic, none of the gait and turning measures collected during on levodopa state were significantly different between fallers and non-fallers. In contrast, digital measures collected in the off levodopa state were significantly different between groups, (average turn velocity, average number of steps to complete a turn, and variability of gait speed, P < 0.03). During daily life, the variability of average turn velocity (P=0.023) was significantly different in fallers than non-fallers. Last, the average number of steps to complete a turn was significantly correlated with the patient-reported outcomes. Digital measures of turning, but not gait, were different in fallers compared to non-fallers with PD, in the laboratory when off medication and during a daily life.

Levodopa Response in Patients With Early Parkinson Disease: Further Observations of the LEAP Study.

The Levodopa in EArly Parkinson's Disease (LEAP) study enabled us to conduct post hoc analyses concerning the effects of levodopa in patients with early Parkinson disease. The LEAP study was a double-blind, placebo-controlled, randomized, delayed-start trial in which patients with early Parkinson disease were randomized to receive levodopa/carbidopa 300/75 mg daily for 80 weeks (early-start group) or to placebo for 40 weeks followed by levodopa/carbidopa 300/75 mg daily for 40 weeks (delayed-start group). We analyzed the effect of levodopa with the Unified Parkinson's Disease Rating Scale on bradykinesia, rigidity, and tremor. At week 80, participants answered 3 questions regarding motor response fluctuations. A total of 222 patients were randomized to the early-start group (mean ± SD age at baseline 64.8 ± 8.7 years; 71% male) and 223 to the delayed-start group (mean ± SD age at baseline 65.5 ± 8.8 years; 69% male). The difference between the early- and delayed-start groups in mean change from baseline to week 4, expressed as Hedges g effect size, was -0.33 for bradykinesia, -0.29 for rigidity, and -0.25 for tremor (for all symptoms indicating a small effect in favor of the early-start group); from baseline to week 22, respectively, -0.49, -0.36, and -0.44 (small to medium effect); and from baseline to week 40, respectively, -0.32, -0.19, and -0.27 (small effect). At 80 weeks, fewer patients in the early-start group (46 of 205 patients, 23%) experienced motor response fluctuations than patients in the delayed-start group (81 of 211, 38%; p < 0.01). In patients with early Parkinson disease, levodopa improves bradykinesia, rigidity, and tremor to the same order of magnitude. For all 3 symptoms, effects were larger at 22 weeks compared with 4 weeks. At 80 weeks, there were fewer patients with motor response fluctuations in the group that had started levodopa earlier. This study provides Class II evidence that the effect of levodopa on bradykinesia, rigidity, and tremor is larger after 22 weeks compared with 4 weeks of treatment. ISRCTN30518857, EudraCT number 2011-000678-72.