Levodopa Replacement Therapy Research Articles

Efficacy of Wearable low-intensity pulsed Ultrasound treatment in the Movement disorder in Parkinson’s disease (the SWUMP trial): protocol for a single-site, double-blind, randomized controlled trial

BackgroundParkinson’s disease (PD) is a progressive, neurodegenerative illness marked by the loss of dopaminergic neurons, causing motor symptoms. Oral levodopa replacement therapy remains the gold standard in the treatment of PD. It is, nevertheless, a symptomatic treatment. There is currently no effective treatment for PD. Therefore, new therapies for PD are highly desirable. Low-intensity pulsed ultrasound (LIPUS) has been shown to improve behavioral functions in PD animal models. It is a new type of neuromodulation approach that combines noninvasiveness with high spatial precision. The purpose of this study is to establish a new clinical protocol for LIPUS in the treatment of movement disorders in patients with PD.MethodsThis protocol is a single-site, prospective, double-blind, randomized controlled trial (RCT). Forty-eight participants with clinically confirmed PD will be randomly allocated to one of two groups: LIPUS group or sham group. All of the participants continue to use pharmacological therapy as a fundamental treatment. The primary outcome is the difference between groups from baseline to 4 months in the change in the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score (part III). The secondary outcomes include the rating scales such as the Mini-Mental State Examination (MMSE), and other three rating scales, and medical examinations including high-density electroencephalography (hdEEG) and functional magnetic resonance imaging (fMRI). The primary safety outcome will be assessed at 4 months, and adverse events will be recorded.DiscussionThis study represents the clinical investigation into the efficacy of therapeutic LIPUS in the treatment of PD for the first time. If LIPUS is determined to be effective, it could offer a practical and innovative means of expanding the accessibility of ultrasound therapy by using a wearable LIPUS device within a home setting.Trial registrationChinese Clinical Trial Registry ChiCTR2100052093. Registered on 17 October 2021.

Theory of mind deficits in Parkinson's disease are not modulated by dopaminergic medication.

Patients with Parkinson's disease (PD) exhibit deficits in social cognition, particularly with respect to Theory of Mind (ToM) capacities. It is unclear whether they are associated with PD-related dopamine deficiency and modulated by levodopa replacement therapy. A total of 15 persons with PD and 13 healthy controls (HC) participated in the study. They performed different neuropsychological tasks, including the Faux Pas Recognition Test (FPRT), assessing different dimensions of cognitive ToM (e.g., detection, inappropriateness, intentions), and the Reading the Mind in the Eyes Test (RMET) as an index of affective ToM. Persons with PD were tested twice, once under their regular treatment and another time after at least 18 h of levodopa withdrawal (MED-ON and MED-OFF, respectively). On either occasion, serum drug levels and motor symptom severity [Unified Parkinson's Disease Rating Scale (UPDRS)] were measured. MED-ON and MED-OFF conditions in patients with PD were confirmed by higher serum drug levels in the former than in the latter state and a corresponding amelioration of the motor deficit. In so doing, no performance difference in any ToM-related task was identified as a function of the levodopa therapy. Generally, patients performed worse than controls in both affective and cognitive ToM tests. Patients with PD have deficits in cognitive and affective ToM. Dopamine replacement, effective for improving the motor condition, does not appear to counteract these dysfunctions.

Parkinsonism and homoeopathic approach

Parkinson's disease, also known as movement disorder, is a disorder of the basal ganglia that causes disturbances in movement and posture but no major paralysis. It has been suggested that oxidative stress plays a significant part in the pathogenesis of disease. Levodopa replacement therapy and dopamine therapy continue to be the cornerstones of Parkinson's disease treatment. Although levodopa and dopamine therapy, in particular, have the ability to improve motor symptoms, motor complications and other non-dopaminergic symptoms continue to be Parkinsons disease worst enemies in terms of therapy options. We can help Parkinson's patients by using therapeutics and homoeopathic principles to avoid motor complications and treat non-dopaminergic symptoms.

Levodopa-Induced Dyskinesia in Parkinson's Disease: Pathogenesis and Emerging Treatment Strategies.

The most commonly used treatment for Parkinson's disease (PD) is levodopa, prescribed in conjunction with carbidopa. Virtually all patients with PD undergo dopamine replacement therapy using levodopa during the course of the disease's progression. However, despite the fact that levodopa is the "gold standard" in PD treatments and has the ability to significantly alleviate PD symptoms, it comes with side effects in advanced PD. Levodopa replacement therapy remains the current clinical treatment of choice for Parkinson's patients, but approximately 80% of the treated PD patients develop levodopa-induced dyskinesia (LID) in the advanced stages of the disease. A better understanding of the pathological mechanisms of LID and possible means of improvement would significantly improve the outcome of PD patients, reduce the complexity of medication use, and lower adverse effects, thus, improving the quality of life of patients and prolonging their life cycle. This review assesses the recent advancements in understanding the underlying mechanisms of LID and the therapeutic management options available after the emergence of LID in patients. We summarized the pathogenesis and the new treatments for LID-related PD and concluded that targeting pathways other than the dopaminergic pathway to treat LID has become a new possibility, and, currently, amantadine, drugs targeting 5-hydroxytryptamine receptors, and surgery for PD can target the Parkinson's symptoms caused by LID.

246 Timing is everything: improving inpatient levodopa administration at the National Hospital for Neurology and Neurosurgery

BackgroundThe mainstay of treatment in Parkinson’s Disease (PD) is levodopa replacement therapy. Variation in the timing of administration can lead to worsening motor fluctuations, falls and medical emergencies.The National Hospital for Neurology and Neurosurgery treats advanced PD patients with complex medical management and deep brain stimulation, admitting up to 250 neurological and 120 neurosurgical PD patients per year.MethodsWe audited the medication administration of PD inpatients over a two month period, aiming to assess the frequency of clinically significant variations and consider how these might be reduced. We included PD patients on levodopa therapy a minimum of 4 times daily, not self-administering medication and admitted for at least 10 days.ResultsA total of 404 episodes of administration were identified. Across all episodes, 18% of levodopa was given later than 30 minutes and 6.5% given more than 30 minutes early. Variations tended to be greater in the neurosurgical division. Survey of the nursing teams identified a number of barriers to timely administration.DiscussionWe plan to implement change by highlighting PD patients at handover, implementing bedside visual aids with medication timings and encouraging the use of medication alarms. The impact of these changes will be re-audited.bryan.ceronie@gmail.com

Compound heterozygous variants in SHQ1 are associated with a spectrum of neurological features, including early-onset dystonia.

SHQ1 is essential for biogenesis of H/ACA ribonucleoproteins, a class of molecules important for processing ribosomal RNAs, modifying spliceosomal small nuclear RNAs and stabilizing telomerase. Components of the H/ACA ribonucleoprotein complex have been linked to neurological developmental defects. Here, we report two sibling pairs from unrelated families with compound heterozygous variants in SHQ1. Exome sequencing was used to detect disease causing variants, which were submitted to 'matching' platforms linked to MatchMaker Exchange. Phenotype comparisons supported these matches. The affected individuals present with early-onset dystonia, with individuals from one family displaying additional neurological phenotypes, including neurodegeneration. As a result of cerebrospinal fluid studies suggesting possible abnormal dopamine metabolism, a trial of levodopa replacement therapy was started but no clear response was noted. We show that fibroblasts from affected individuals have dramatic loss of SHQ1 protein. Variants from both families were expressed in Saccharomyces cerevisiae, resulting in a strong reduction in H/ACA snoRNA production and remarkable defects in rRNA processing and ribosome formation. Our study identifies SHQ1 as associated with neurological disease, including early-onset dystonia, and begins to delineate the molecular etiology of this novel condition.

Current Status and Future Prospects of Therapeutic Development of Parkinson's Disease

There has been remarkable progress in the search for Parkinson's disease therapies. However, L-dopa replacement therapy remains the gold standard despite drawbacks that include wearing off and dyskinesias. Devices such as continuous infusion pumps and new dosage forms have been developed to improve the treatment response to L-dopa. Simultaneously, many new drugs that control these side effects have been developed. In addition, progression-suppressing therapeutic agents, such as α-synuclein targeting nucleic acid therapies and antibody therapies are in development all over the world. Biomarkers are needed to assess the effects of these therapies; hence, biomarker development is an urgent task.

In Silico Studies Targeting G-protein Coupled Receptors for Drug Research Against Parkinson's Disease.

Parkinson’s Disease (PD) is a long-term neurodegenerative brain disorder that mainly affects the motor system. The causes are still unknown, and even though currently there is no cure, several therapeutic options are available to manage its symptoms. The development of novel anti-parkinsonian agents and an understanding of their proper and optimal use are, indeed, highly demanding. For the last decades, L-3,4-DihydrOxyPhenylAlanine or levodopa (L-DOPA) has been the gold-standard therapy for the symptomatic treatment of motor dysfunctions associated to PD. However, the development of dyskinesias and motor fluctuations (wearing-off and on-off phenomena) associated with long-term L-DOPA replacement therapy have limited its antiparkinsonian efficacy. The investigation for non-dopaminergic therapies has been largely explored as an attempt to counteract the motor side effects associated with dopamine replacement therapy. Being one of the largest cell membrane protein families, G-Protein-Coupled Receptors (GPCRs) have become a relevant target for drug discovery focused on a wide range of therapeutic areas, including Central Nervous System (CNS) diseases. The modulation of specific GPCRs potentially implicated in PD, excluding dopamine receptors, may provide promising non-dopaminergic therapeutic alternatives for symptomatic treatment of PD. In this review, we focused on the impact of specific GPCR subclasses, including dopamine receptors, adenosine receptors, muscarinic acetylcholine receptors, metabotropic glutamate receptors, and 5-hydroxytryptamine receptors, on the pathophysiology of PD and the importance of structure- and ligand-based in silico approaches for the development of small molecules to target these receptors.

The Ceruloplasmin Transferrin Ratio in the Blood of Patients at Different Stages of Parkinson’s Disease

The ratio of the concentrations of Cu2+-ceruloplasmin/Fe3+-transferrin in the blood plasma of 54 patients at different stages of Parkinson’s disease treated and not treated with L-DOPA was estimated by EPR-spectroscopy. It was established that in patients who suffer from Parkinson’s disease, the value of ceruloplasmin/ transferrin increased by 157% in comparison with the control group of clinically healthy people of the same age group. In patients with Parkinson’s disease, the ratio of ceruloplasmin/transferrin increased at stage 1 of the disease by 119%, at stage 2 by 117%, and at stage 3 by 135% in comparison with the control group. There was no statistically significant difference between the ratio of ceruloplasmin/transferrin in patients who received and did not recive L-DOPA replacement therapy. These data reveal changes in the functioning of the ceruloplasmin: transferrin system, which decreases the content of toxic ions of Fe2+ in the plasma of patients with Parkinson’s disease. These changes are a pathogenetically significant factor of Parkinson’s disease at all stages of the disease.

Presynaptic effects of levodopa and their possible role in dyskinesia.

Levodopa replacement therapy has long provided the most effective treatment for Parkinson's disease (PD). We review how this dopamine (DA) precursor enhances dopaminergic transmission by providing a greater sphere of neurotransmitter influence as a result of the confluence of increased quantal size and decreased DA reuptake, as well as loading DA as a false transmitter into surviving serotonin neuron synaptic vesicles. We further review literature on how presynaptic dysregulation of DA release after l-dopa might trigger dyskinesias in PD patients.

IRC-082451, a Novel Multitargeting Molecule, Reduces L-DOPA-Induced Dyskinesias in MPTP Parkinsonian Primates

The development of dyskinesias following chronic L-DOPA replacement therapy remains a major problem in the long-term treatment of Parkinson’s disease. This study aimed at evaluating the effect of IRC-082451 (base of BN82451), a novel multitargeting hybrid molecule, on L-DOPA-induced dyskinesias (LIDs) and hypolocomotor activity in a non-human primate model of PD. IRC-082451 displays multiple properties: it inhibits neuronal excitotoxicity (sodium channel blocker), oxidative stress (antioxidant) and neuroinflammation (cyclooxygenase inhibitor) and is endowed with mitochondrial protective properties. Animals received daily MPTP injections until stably parkinsonian. A daily treatment with increasing doses of L-DOPA was administered to parkinsonian primates until the appearance of dyskinesias. Then, different treatment regimens and doses of IRC-082451 were tested and compared to the benchmark molecule amantadine. Primates were regularly filmed and videos were analyzed with specialized software. A novel approach combining the analysis of dyskinesias and locomotor activity was used to determine efficacy. This analysis yielded the quantification of the total distance travelled and the incidence of dyskinesias in 7 different body parts. A dose-dependent efficacy of IRC-082451 against dyskinesias was observed. The 5 mg/kg dose was best at attenuating the severity of fully established LIDs. Its effect was significantly different from that of amantadine since it increased spontaneous locomotor activity while reducing LIDs. This dose was effective both acutely and in a 5-day sub-chronic treatment. Moreover, positron emission tomography scans using radiolabelled dopamine demonstrated that there was no direct interference between treatment with IRC-082451 and dopamine metabolism in the brain. Finally, post-mortem analysis indicated that this reduction in dyskinesias was associated with changes in cFOS, FosB and ARC mRNA expression levels in the putamen. The data demonstrates the antidyskinetic efficacy of IRC-082451 in a primate model of PD with motor complications and opens the way to the clinical application of this treatment for the management of LIDs.

5 Monomelic Amyotrophy and Parkinson’s disease: Possible correlations?

Benign Monomelic Amyotrophy (BMA) is a sporadic condition characterized by a neurogenic amyotrophy that affects a single either upper or lower limb; typically the disease is confined to second motoneuron involvement without cerebellar, pyramidal and cognitive signs; extrapyramidal features are not reported in BMA. We describe the case of a patient who experienced weakness and muscle atrophy in the right limb which starts approximately 5 years ago and progressed over the following 4 years. There was no history of poliomyelitis or familial neuromuscolar diseases. He denied any sensory symptoms; neurological examination showed marked amyotrophy of the right calf and mild amyotrophy of the right thigh with mild-to-moderate weakness; cranial nerves, sensory, pyramidal and cerebellar systems were normal. Needle electromyography revealed fibrillation potentials (acute denervation), polyfasic action potential, increased amplitude and long-duration of MUAPs and reduced recruitment pattern (chronic partial denervation and reinnervation). Transcranial magnetic stimulation was normal. MRI of the lower limbs detected severe right leg muscle atrophy and muscular replacement with adipose tissue. After one year extrapyramidal signs were observed as follows: hypomimia, bradykinesia, akinesia, axial and bilateral arm rigidity with decreased arm swing, postural instability, without cerebellar signs or cognitive decline. SPECT DAT SCAN examination showed reduced dopaminergic innervation in the striatum on both sides. We observed improvement of extrapyramidal features with Levodopa replacement therapy. Extrapyramidal dysfunctions are uncommon but recognized feature in motor neuron disease for which the pathological substrate is uncertain. To our knowledge this is the first description of BMA associated with Parkinsonism.

Levodopa/benserazide microspheres reduced levodopa-induced dyskinesia by downregulating phosphorylated GluR1 expression in 6-OHDA-lesioned rats

BackgroundLevodopa is the gold standard in the treatment of Parkinson’s disease (PD). However, long-term levodopa replacement therapy is accompanied by abnormal involuntary movements (AIMs), known as levodopa-induced dyskinesia (LID). Until now, the precise mechanisms of LID were only partially understood. Previous studies have shown that continuous dopamine stimulation was helpful in reducing the expression of LID. In addition to dopamine D1 receptor, glutamatergic receptors such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor also contribute to the expression of LID. The current authors have previously reported that levodopa/benserazide-loaded microspheres could ameliorate the expression of LID by reducing the protein kinase A signaling pathway in dyskinetic rats. However, whether AMPA receptor is involved in the mechanism by which levodopa/benserazide-loaded microspheres ameliorate the expression of LID in dyskinetic rats was unknown.MethodsIn the present study, as reported previously, levodopa and benserazide were loaded by poly(lactic-co-glycolic acid) microspheres, which can release levodopa and benserazide in a sustained manner. 6-Hydroxydopamine was injected into the right medial forebrain bundle to produce a rat model of PD. Then valid PD rats were treated with levodopa plus benserazide for 3 weeks to induce a rat model of LID. Dyskinetic rats were treated with levodopa/beserazide-loaded microspheres containing levodopa (6 mg/kg) plus benserazide (15 mg/kg) or same dose of levodopa plus benserazide. Abnormal involuntary movements were measured in rats on days 1, 5, 10, 15, and 20 during the treatment. The levels of GluR1 at serine-831 (pGluR1S831) and serine-845 (pGluR1S845) were determined by Western blot. Arc and proenkephalin (Penk) levels were measured by real-time polymerase chain reaction.ResultsThree-week levodopa plus benserazide treatment induced dyskinesia in PD rats. Levodopa/benserazide-loaded microsphere-treated dyskinetic rats showed lower AIM scores than levodopa plus benserazide-treated dyskinetic rats. Microsphere treatment downregulated the phosphrylated levels of pGluR1S831 and pGluR1S845 in the striatum of dyskinetic rats. In addition, microsphere treatment reduced the levels of Arc and Penk.ConclusionThese data indicated that levodopa/benserazide-loaded microspheres could be used to ameliorate the expression of LID by reducing the expression of pGluR1S831 and pGluR1S845 as well as Arc and Penk.

Parkinsonism in cirrhosis: pathogenesis and current therapeutic options

Acquired hepatolenticular degeneration, also known as "Parkinsonism in cirrhosis" is characterized by extrapyramidal symptoms including hypokinesia, dystonia and rigidity that are rapidly progressive and may be independent of the severity of cognitive dysfunction. Magnetic resonance imaging reveals T1-weighted hyperintense signals in both globus pallidus and substantia nigra. Estimates of the prevalence of Parkinsonism in cirrhosis have been reported as high as 21 %. The cause of Parkinsonism in cirrhosis has been attributed to manganese deposition in basal ganglia structures, leading to the dysfunction of the dopaminergic neurotransmitter system. In particular, there is evidence from both spectroscopic and biochemical investigations for damage to (or dysfunction of) presynaptic dopamine transporters together with a loss of post-synaptic dopamine receptors in basal ganglia of affected patients. Therapeutic options are limited; ammonia-lowering strategies are without substantial benefit, and an effective manganese chelator is not available. In many patients, L-Dopa replacement therapy and the dopamine receptor agonist bromocriptine are beneficial, and liver transplantation is generally effective. However, reports of post-transplant residual extrapyramidal symptoms suggest an element of irreversibility in some cases.

B28 Neural mechanisms underlying the dysfunction of the methamphetamine-sensitive circadian oscillator (MASCO) in a mouse model of Huntington's disease

<h3>Background</h3> A progressive disintegration of the rest-activity rhythm is seen in the R6/2 mouse model of Huntington9s disease. Circadian rhythms are orchestrated by the master clock located within the suprachiasmatic nucleus, but rest-activity rhythms can also be regulated by extra-suprachiasmatic nucleus oscillators such as the methamphetamine-sensitive circadian oscillator (MASCO). The MASCO is activated by placing WT mice under constant darkness and treating them chronically with methamphetamine (MAP). MAP alters the circadian rhythm measured via locomotor activity by significantly increasing the period. The MASCO is dysfunctional in presymptomatic R6/2 mice but can be partially restored by L-DOPA replacement therapy. This suggests a presymptomatic abnormality of the catecholaminergic systems in R6/2 mice. <h3>Aims</h3> Our aim was to investigate the neuronal mechanism underlying the MASCO and to understand the contribution that a deficient MASCO makes to the progressive disintegration of the rest-activity rhythm observed in R6/2 mice. <h3>Methods</h3> WT mice were placed under constant darkness. The rest-activity rhythm was measured continuously using passive infrared movement sensors. Mice were given a chronic low dose of MAP (0.005%) via the drinking water to induce the MASCO. Some groups were also treated chronically with the D₂ receptor antagonist haloperidol (0.01 or 0.05 mg/kg/day), reserpine (1 mg/kg/day) or cocaine (20 or 30 mg/kg/day). <h3>Results</h3> Haloperidol did not block the MASCO, suggesting that D₂ receptors are not an essential mediator of this oscillator. Depletion of catecholamines using chronic reserpine treatment also did not fully block the MASCO in WT mice. Finally, cocaine given chronically did not induce MASCO-like changes in activity. <h3>Conclusion</h3> Together these results suggest that dopamine neurotransmission alone does not underlie the generation of the MASCO. More specific drugs or lesion studies need to be tested before we can understand the mechanisms.

Investigation of the antidyskinetic site of action of metabotropic and ionotropic glutamate receptor antagonists. Intracerebral infusions in 6-hydroxydopamine-lesioned rats with levodopa-induced dyskinesia

Long-term levodopa replacement therapy in Parkinson's disease is confounded by abnormal involuntary movements, known as levodopa induced dyskinesia (LID). Dysfunctional glutamatergic neurotransmission has been implicated in the pathogenesis of LID making metabotropic and ionotropic glutamate receptors attractive novel therapeutic targets. The objective of the present study was to investigate the antidyskinetic site of action of different glutamate receptor antagonists in the brain. For that purpose, metabotropic glutamate subtype 5 (3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride, MTEP), NMDA NR2B selective ((aR,bS)-a-(4-Hydroxyphenyl)-b-methyl-4-(phenylmethyl)-1-piperidinepropanol maleate, Ro 25-6981) and AMPA (2,3-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt, NBQX) receptor antagonists or saline were administered by intracerebral infusion in the caudate–putamen (CPu), the substantia nigra zona reticulata (SNr) or the subthalamic nucleus (STN) of 6-hydroxydopamine-lesioned rats exhibiting LID. Dyskinesia was assessed with the modified version of the rat Abnormal Involuntary Movements scale (AIMS). Ro 25-6981 and to a lesser extent NBQX improved dyskinesia (82% and 19% reduction in AIM score respectively) after infusion in the caudate–putamen. None of the three drugs managed to noticeably reduce AIM score after infusion in the SNr. MTEP was the only drug that produced a reduction in AIM score (48%) when infused in STN. In conclusion, while the striatum proved important in the antidyskinetic action of NMDA and AMPA receptor antagonists, the results of this study highlight also the importance of the metabotropic glutamate receptors that reside in the STN as therapeutic targets in the treatment of LID.

Endocannabinoid Modulation of Dopaminergic Motor Circuits

There is substantial evidence supporting a role for the endocannabinoid system as a modulator of the dopaminergic activity in the basal ganglia, a forebrain system that integrates cortical information to coordinate motor activity regulating signals. In fact, the administration of plant-derived, synthetic or endogenous cannabinoids produces several effects on motor function. These effects are mediated primarily through the CB1 receptors that are densely located in the dopamine-enriched basal ganglia networks, suggesting that the motor effects of endocannabinoids are due, at least in part, to modulation of dopaminergic transmission. On the other hand, there are profound changes in CB1 receptor cannabinoid signaling in the basal ganglia circuits after dopamine depletion (as happens in Parkinson’s disease) and following l-DOPA replacement therapy. Therefore, it has been suggested that endocannabinoid system modulation may constitute an important component in new therapeutic approaches to the treatment of motor disturbances. In this article we will review studies supporting the endocannabinoid modulation of dopaminergic motor circuits.

Cerebral blood flow changes induced by pedunculopontine nucleus stimulation in patients with advanced Parkinson's disease: A [15O] H2O PET study

Patients with advanced Parkinson's disease (PD) develop disabling axial symptoms, including gait disturbances, freezing and postural instability poorly responsive to levodopa replacement therapy. The pedunculopontine nucleus (PPN) is involved in locomotion, control of posture, and behavioral states [i.e. wakefulness, rapid eye movement sleep]. Recent reports suggested that PPN modulation with deep brain stimulation (DBS) may be beneficial in the treatment of axial symptoms. However, the mechanisms underlying these effects are still unknown. We used [(15)O] H(2)O PET to investigate regional cerebral blood flow in three patients with advanced PD who underwent a new experimental surgical procedure with implantation of unilateral PPN-DBS. Patients were studied Off-medication with stimulator Off and On, both at rest and during a self-paced alternating motor task of the lower limbs. We used SPM2 for imaging data analysis, threshold P < 0.05 corrected at the cluster level. Stimulation induced significant regional cerebral blood flow increment in subcortical regions such as the thalamus (P < 0.006), cerebellum (P < 0.001), and midbrain region (P < 0.001) as well as different cortical areas involving medial sensorimotor cortex extending into caudal supplementary motor area (BA 4/6; P < 0.001). PPN-DBS in advanced PD resulted in blood flow and presumably neuronal activity changes in subcortical and cortical areas involved in balance and motor control, including the mesencephalic locomotor region (e.g. PPN) and closely interconnected structures within the cerebello-(rubro)-thalamo-cortical circuit. Whether these findings are associated with the DBS-PPN clinical effect remains to be proven. However, they suggest that PPN modulation may induce functional changes in neural networks associated with the control of lower limb movements.

D2 receptor stimulation, but not D1, restores striatal equilibrium in a rat model of Parkinsonism

In Parkinson's disease dopamine depletion imbalances the two major output pathways of the striatum. L-DOPA replacement therapy is believed to correct this imbalance by providing effective D1 and D2 receptor stimulation to striatonigral and striatopallidal neurons, respectively. Here we tested this assumption in the rat model of Parkinsonism by monitoring the spike response of identified striatal neurons to cortical stimulation. As predicted, in 6-hydroxydopamine lesioned rats we observed that L-DOPA (6 mg/kg + benserazide), apomorphine and the D2 agonist quinpirole (0.5 mg/kg i.p.) counteract the enhanced responsiveness of striatopallidal neurons. Unexpectedly, the depressed responsiveness of striatonigral neurons was corrected by quinpirole whereas D1 stimulation exerted no (apomorphine, cPB) or worsening effects (L-DOPA, SKF38393 10 mg/kg). Therefore, quinpirole, but not D1 stimulation, restores functional equilibrium between the two striatal output pathways. Our results might explain the therapeutic effect of D2-based medications in Parkinson's disease.

Chronic intermittent L‐DOPA treatment induces changes in dopamine release

3,4-Dihydroxyphenyl-l-alanine (l-DOPA)-induced dyskinesia often develops as a side effect of chronic l-DOPA therapy. This study was undertaken to investigate dopamine (DA) release upon l-DOPA treatment. Chronoamperometric measurements were performed in unilaterally DA-depleted rats, chronically treated with l-DOPA, resulting in dyskinetic and non-dyskinetic animals. Normal and lesioned l-DOPA naïve animals were used as controls. Potassium-evoked DA releases were significantly reduced in intact sides of animals undertaken chronic l-DOPA treatment, independent on dyskinetic behavior. Acute l-DOPA further attenuated the amplitude of the DA release in the control sides. In DA-depleted striata, no difference was found in potassium-evoked DA releases, and acute l-DOPA did not affect the amplitude. While immunoreactivity to serotonin uptake transporter was higher in lesioned striata of animals displaying dyskinetic behavior, no correlation could be documented between serotonin transporter-positive nerve fiber density and the amplitude of released DA. In conclusions, the amplitude of potassium-evoked DA release is attenuated in intact striatum after chronic intermittent l-DOPA treatment. No change in amplitude was found in DA-denervated sides of either dyskinetic or non-dyskinetic animals, while release kinetics were changed. This indicates the importance of studying DA release dynamics for the understanding of both beneficial and adverse effects of l-DOPA replacement therapy.