Nigrostriatal Dopamine Function Research Articles

Diagnostic value of micrographia in Parkinson’s disease: a study with [123I]FP-CIT SPECT

Micrographia is a common symptom of Parkinson’s disease (PD), and it may precede other motor symptoms. Despite the high prevalence of micrographia in PD, its neurobiological mechanisms are not known. Given that levodopa may alleviate consistent micrographia and that nondopaminergic essential tremor (ET) is not associated with micrographia, micrographia could possibly be used as an ancillary diagnostic method that reflects nigrostriatal dopamine function. We evaluated the usefulness of micrographia as a simple one-sentence writing test in differentiating PD from ET. A total of 146 PD patients, 42 ET patients and 38 healthy controls provided writing samples and were scanned with brain [123I]FP-CIT dopamine transporter (DAT) SPECT imaging with ROI-based and voxelwise analyses. The diagnostic accuracy of micrographia was evaluated and compared to that of DAT binding. Compared to ET and healthy controls, PD patients showed micrographia (consistent, 25.6% smaller area of handwriting sample in PD compared to ET, p = 0.002, and 27.2% smaller area of handwriting compared to healthy controls, p = 0.004). PD patients showed 133% more severe progressive micrographia compared with ET patients (median b = − 0.14 in PD, b = − 0.06 in ET, p = 0.021). In early unmedicated cognitively normal patients, consistent micrographia showed 71.2% specificity and 87.5% sensitivity in PD versus ET differentiation, but micrographia had no correlation with striatal or extrastriatal [123I]FP-CIT binding in patients with PD. The one-sentence micrographia test shows moderately good accuracy in PD versus ET differentiation. The severity of micrographia has no relationship with DAT binding, suggesting nondopaminergic mechanism of micrographia in PD.ClinicalTrials.gov identifier: NCT02650843 (NMDAT study).

GABAergic and glutamatergic effects on nigrostriatal and mesolimbic dopamine release in the rat.

In this review, a series of experiments is presented, in which γ-amino butyric acid (GABA)ergic and glutamatergic effects on dopamine function in the rat nigrostriatal and mesolimbic system was systematically assessed after pharmacological challenge with GABAA receptor (R) and and N-methyl d-aspartate (NMDA)R agonists and antagonists. In these studies, [123I]iodobenzamide binding to the D2/3R was mesured in nucleus accumbens (NAC), caudateputamen (CP), substantia nigra/ventral tegmental area (SN/VTA), frontal (FC), motor (MC) and parietal cortex (PC) as well as anterior (aHIPP) and posterior hippocampus (pHIPP) with small animal SPECT in baseline and after injection of either the GABAAR agonist muscimol (1mg/kg), the GABAAR antagonist bicuculline (1mg/kg), the NMDAR agonist d-cycloserine (20mg/kg) or the NMDAR antagonist amantadine (40mg/kg). Muscimol reduced D2/3R binding in NAC, CP, SN/VTA, THAL and pHIPP, while, after amantadine, decreases were confined to NAC, CP and THAL. In contrast, d-cycloserine elevated D2/3R binding in NAC, SN/VTA, THAL, frontal cortex, motor cortex, PC, aHIPP and pHIPP, while, after bicuculline, increases were confined to CP and THAL. Taken together, similar actions on regional dopamine levels were exterted by the GABAAR agonist and the NMDAR antagonist on the one side and by the GABAAR antagonist and the NMDAR agonist on the other, with agonistic action, however, affecting more brain regions. Thereby, network analysis suggests different roles of GABAARs and NMDARs in the mediation of nigrostriatal, nigrothalamocortical and mesolimbocortical dopamine function.

Amantadine enhances nigrostriatal and mesolimbic dopamine function in the rat brain in relation to motor and exploratory activity

PurposeThe present study assessed the influence of the NMDA receptor (R) antagonist amantadine (AMA) on cerebral dopamine D2/3R binding in relation to motor and exploratory activity in the rat. MethodsD2/3R binding was determined in anaesthetized animals with small animal SPECT in baseline and after challenge with AMA (10 or 40 mg/kg) using [123I]IBZM as radioligand. Immediately post-challenge and prior to radioligand administration, motor/exploratory behaviors were assessed for 30 min in an open field. Each rat underwent measurements with a dedicated small animal MRI in order to gain anatomical information. Regions of interest were defined on SPECT-MRI overlays. The regional binding potentials in baseline and post-challenge were estimated by computing ratios of the specifically bound compartments to the cerebellar reference region. Results40 mg/kg AMA reduced D2/3R binding in nucleus accumbens, caudateputamen and thalamus, while 10 mg/kg decreased D2/3R binding in the anterodorsal hippocampus. The higher dose decreased ambulatory activity, rearing and grooming, but elevated sitting and head-shoulder motility relative to both vehicle and the lower dose in the first 15 min post-challenge. ConclusionsResults showed reductions of D2/3R binding in regions of the nigrostriatal and mesolimbic system after challenge with AMA, which reflect an increased availability of dopamine. Thereby, an inverse relationship between nigrostriatal and mesolimbic dopamine and motor/exploratory activity can be inferred. Findings may be relevant for the treatment of neurological and psychiatric conditions such as Parkinson's disease, Huntington's disease or schizophrenia, which are characterized by both dopaminergic and glutamatergic dysfunction.

Dopamine transporter availability reflects gastrointestinal dysautonomia in early Parkinson disease

BackgroundConstipation is a prodromal feature of Parkinson's disease (PD) and the gastrointestinal (GI) tract is implicated in the pathogenesis of PD. However, no studies have demonstrated ante-mortem relationships between nigrostriatal dysfunction and GI dysautonomia in PD. MethodsThe Scale for Outcomes in Parkinson's disease for Autonomic Symptoms (SCOPA-AUT) assesses dysautonomia in the multi-center Parkinson's Progression Marker Initiative (PPMI). We used linear mixed-effects models and reliable change indices (RCIs) to examine longitudinal associations between dysautonomia and dopamine transporter (DAT) striatal binding ratios (SBRs) measured by single-photon emission computerized tomography in PPMI participants over four years (n = 397 at baseline). ResultsAdjusted mixed-models of longitudinal data showed that constipation—but not orthostatic hypotension or urinary dysfunction—was associated with reduced SBR in both caudate (P < 0.001) and putamen (P = 0.040). In both regions, SBR reductions between baseline and 4-year follow-up were significant and measurable (P < 0.0001), with larger decline and variance in the caudate nucleus. Four-year change in caudate—but not putaminal—SBR was significantly associated with RCI-indicated progression of GI dysautonomia (P = 0.031), but not other types of dysautonomia. These associations remained after adjusting for the use of medications or supplements to control constipation. Consistent with prior PPMI reports, motor impairment progression was not associated with SBR reduction. ConclusionsGI dysautonomia correlates with reductions in DAT availability; constipation is most closely associated with caudate-DAT reduction. Worsening GI-dysautonomia and reduced bowel movements may accompany advancing nigral degeneration or changes in nigrostriatal dopamine function.

Lycium barbarum Polysaccharide Promotes Nigrostriatal Dopamine Function by Modulating PTEN/AKT/mTOR Pathway in a Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Murine Model of Parkinson's Disease.

To investigate the effects of Lycium barbarum polysaccharide (LBP) on pathological symptoms and behavioral deficits in a Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) mouse model. The therapeutic effects of LBP were monitored with an Open field test, a Rotarod test and a Morris water maze test. We also investigated the mechanisms with qRT-PCR and Western blotting analyses. After a relatively short-term LBP treatment, the total distance and walking time of PD mice significantly increased. The staying duration on the rod of PD mice increased in the Rotarod test. LBP can up-regulate levels of SOD2, CAT and GPX1 and inhibit the abnormal aggregation of α-synuclein induced by MPTP. LBP treatment can also up-regulate the phosphorylation of AKT and mTOR, and may play its protective role by activating the PTEN/AKT/mTOR signaling axis. These results suggest that LBP can effectively alleviate the degeneration in the nigrostriatal system induced by MPTP treatment. It may be a potential candidate for the treatment of Parkinson's disease.

Assessment of neuroinflammation in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study

Findings from longitudinal follow-up studies in patients with idiopathic rapid-eye-movement sleep behaviour disorder (IRBD) have shown that most patients will eventually develop the synucleinopathies Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. Neuroinflammation in the form of microglial activation is present in synucleinopathies and is a potential therapeutic target to halt or delay the neurodegenerative process. We aimed to investigate whether neuroinflammation is present in patients with IRBD and its possible relation to nigrostriatal dopamine function. In this prospective, case-control, PET study, patients with IRBD and no clinical evidence of parkinsonism and cognitive impairment were recruited from tertiary sleep centres in Spain (Barcelona) and Denmark (Aarhus). We included patients with polysomnography-confirmed IRBD according to established criteria. Healthy controls were recruited through newspaper advertisements. Controls had no motor or cognitive complaints, a normal neurological examination, and a mean group age similar to the IRBD group. In patients with IRBD, we assessed microglial activation in the substantia nigra, putamen, and caudate with 11C-PK11195 PET, and dopaminergic axon terminal function in the putamen and caudate with 18F-DOPA PET. Controls underwent either 11C-PK11195 PET or 18F-DOPA PET. We compared 18F-DOPA uptake and 11C-PK11195 binding potential between groups with an unpaired, two-tailed Student's t test. Between March 23, 2015, and Oct 19, 2016, we recruited 20 consecutive patients with IRBD and 19 healthy controls. 11C-PK11195 binding was increased on the left side of the substantia nigra in patients with IRBD compared with controls (Student's t test, mean difference 0·153 [95% CI 0·055 to 0·250], p=0·003), but not on the right side (0·121 [-0·007 to 0·250], p=0·064). 11C-PK11195 binding was not significantly increased in the putamen and caudate of patients with IRBD. 18F-DOPA uptake was reduced in IRBD in the left putamen (-0·0032 [-0·0044 to -0·0021], p<0·0001) and right putamen (-0·0032 [-0·0044 to -0·0020], p<0·0001), but not in the caudate. In patients with IRBD, increased microglial activation was detected by PET in the substantia nigra along with reduced dopaminergic function in the putamen. Further studies, including more participants than were in this study and longitudinal follow-up, are needed to support our findings and evaluate whether the presence of activated microglia in patients with IRBD represents a marker of short-term conversion to a clinically defined synucleinopathy in the near future. Danish Council for Independent Research, Instituto de Salud Carlos III (Spain).

Progression of nonmotor symptoms in subgroups of patients with non-dopamine-deficient Parkinsonism.

Ten to fifteen percent of Parkinson's disease (PD) patients recruited to clinical trials have scans without evidence of dopaminergic deficit, whose presence represents a heterogeneous patient population. A cohort of 41 patients with parkinsonism and scans without evidence of dopaminergic deficit at baseline, were subdivided into groups according to their final clinical diagnoses and nigrostriatal dopamine function assessed after 2 years of study. At follow up, 23 patients had clinically probable PD or unclassified parkinsonism with normal nigrostriatal dopamine imaging ("true" scans without evidence of dopaminergic deficit), nine were diagnosed with another tremulous condition, five had psychogenic parkinsonism, and four had phenoconverted to PD with reduced nigrostriatal dopamine function. We analyzed nonmotor symptoms at baseline and follow-up in subgroups of patients with scans without evidence of dopaminergic deficit in comparison with a random sample of 62 PD patients and 195 healthy controls (HCs). All patients were enrolled in the Parkinson's Progressive Marker's Initiative. Patients who had true scans without evidence of dopaminergic deficit had more severe rapid eye movement sleep disorder, depression, anxiety, and autonomic dysfunction than HCs in addition to more frequent depressive symptoms and worse cardiovascular dysfunction than patients with PD (P = 0.038, P = 0.047, respectively). Patients with true scans without evidence of dopaminergic deficit had normal olfaction that was significantly better than that of patients with PD (P < 0.001). Subgroup analysis of the cohort with scans without evidence of dopaminergic deficit revealed that all patients shared similar nonmotor features irrespective of their final clinical diagnoses. Follow-up of subject groups showed stable nonmotor symptoms over 2 years of study. At an early symptomatic stage, patients with scans without evidence of dopaminergic deficit and long-standing parkinsonism exhibit nonmotor features that differ from those of patients with PD on mood and cardiovascular and olfactory function, but remain similar to patients with scans without evidence of dopaminergic deficit with alternative final diagnoses.

A simple algorithm for subregional striatal uptake analysis with partial volume correction in dopaminergic PET imaging

In positron emission tomography (PET) of the dopaminergic system, quantitative measurements of nigrostriatal dopamine function are useful for differential diagnosis. A subregional analysis of striatal uptake enables the diagnostic performance to be more powerful. However, the partial volume effect (PVE) induces an underestimation of the true radioactivity concentration in small structures. This work proposes a simple algorithm for subregional analysis of striatal uptake with partial volume correction (PVC) in dopaminergic PET imaging. The PVC algorithm analyzes the separate striatal subregions and takes into account the PVE based on the recovery coefficient (RC). The RC is defined as the ratio of the PVE-uncorrected to PVE-corrected radioactivity concentration, and is derived from a combination of the traditional volume of interest (VOI) analysis and the large VOI technique. The clinical studies, comprising 11 patients with Parkinson's disease (PD) and 6 healthy subjects, were used to assess the impact of PVC on the quantitative measurements. Simulations on a numerical phantom that mimicked realistic healthy and neurodegenerative situations were used to evaluate the performance of the proposed PVC algorithm. In both the clinical and the simulation studies, the striatal-to-occipital ratio (SOR) values for the entire striatum and its subregions were calculated with and without PVC. In the clinical studies, the SOR values in each structure (caudate, anterior putamen, posterior putamen, putamen, and striatum) were significantly higher by using PVC in contrast to those without. Among the PD patients, the SOR values in each structure and quantitative disease severity ratings were shown to be significantly related only when PVC was used. For the simulation studies, the average absolute percentage error of the SOR estimates before and after PVC were 22.74% and 1.54% in the healthy situation, respectively; those in the neurodegenerative situation were 20.69% and 2.51%, respectively. We successfully implemented a simple algorithm for subregional analysis of striatal uptake with PVC in dopaminergic PET imaging. The PVC algorithm provides an accurate measure of the SOR in the entire striatum and its subregions, and improves the correlation between the SOR values and the clinical disease severity of PD patients.

Short-term atrazine exposure causes behavioral deficits and disrupts monoaminergic systems in male C57BL/6 mice

Excessive exposure to the widely used herbicide atrazine (ATR) affects several organ systems, including the brain, where neurochemical alterations reflective of dopamine (DA) circuitry perturbation have been reported. The present study aimed to investigate effects of short-term oral exposure to a dose-range (0, 5, 25, 125, or 250mg/kg) of ATR on behavioral, neurochemical, and molecular indices of toxicity in adult male C57BL/6 mice. The experimental paradigm included open field, pole and grip tests (day 4), novel object recognition (NOR) and forced swim test (FST; day 9), followed by tissue collection 4h post dosing on day 10. After 4days of exposure, ATR decreased locomotor activity (≥125mg/kg). On day 9, ATR-exposed mice exhibited dose-dependent decreased performance in the NOR test (≥25mg/kg) and spent more time swimming and less time immobile during the FST (≥125mg/kg). Neurochemically, short-term ATR exposure increased striatal DA and DA turnover (its metabolite homovanillic acid [HVA] and the HVA/DA ratio; ≥125mg/kg). In addition, ATR exposure increased the levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the striatum (≥125mg/kg) and it also increased DA turnover (≥125mg/kg), 5-HIAA (125mg/kg), and norepinephrine (≥125mg/kg) levels in the prefrontal cortex. In the hippocampus, the only effect of ATR was to increase the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG; 250mg/kg). At the molecular level, the expression of key striatal (protein) or nigral (mRNA) markers associated with nigrostriatal DA function, such as tyrosine hydroxylase, DA transporter, vesicular monoamine transporter 2, and DA receptors, was not affected by ATR. These results indicate that short-term ATR exposure targets multiple monoamine pathways at the neurochemical level, including in the striatum, and induces behavioral abnormalities suggestive of impaired motor and cognitive functions and increased anxiety. Impaired performance in the NOR behavioral test was the most sensitive endpoint affected by ATR; this should be taken into consideration for future low-dose ATR studies and for the assessment of risk associated with overexposure to this herbicide.

A historical justification for and retrospective analysis of the systematic application of light therapy in Parkinson’s disease

For the past 40 years the primary purpose of therapeutics for Parkinson's disease (PD) has been to replace deficient dopamine (DA) in the nigrostriatal dopamine (NSD) system. Even in the presence of limited efficacy, abundant side effects and impoverished quality of life, the involvement of other systems in the aetiology and treatment of this disorder has been sorely neglected and the excessive use of DA replacement therapy (DART) continues on a global basis. Recent scientific work suggests that the retina plays a major role in NSD function and intimates light therapy in the management of PD. After a thorough review of historical evidence supporting this contention, a retrospective, open-label study on 129 PD patients, whereby they were monitored for a period extending for a few months to eight years, was carried out. Primary motor and non-motor symptoms were monitored using an objectified global rating scale and timed motor tests that were assessed at regular intervals for the duration of the study. Thirty-one patients with other neurological disorders (OND) served as controls to determine whether any therapeutic effects seen with light were generalizable across other conditions. Patients were classified as compliant (COM), semi-compliant (SCOM), or early quit (EQUIT; prematurely discontinued treatment). EQUIT patients showed deterioration, while the COM group improved on most parameters. The SCOM patients were not as good as the COM group. The OND group showed significant improvement in depression and insomnia, but exposure to light did not improve motor function. The total drug burden of PD patients maintained on light was less with fewer side effects than SCOM or EQUIT groups. These results confirm the value of the strategic application of light therapy with controlled doses of DART in PD and warrants further controlled investigation. That the symptomatic improvement continued as long patients remained in the program suggests that exposure to light, under a strict daily regimen, combined with controlled DART, actively slows or arrests the progressive degenerative process underlying PD.

Insulin resistance impairs nigrostriatal dopamine function

Clinical studies have indicated a link between Parkinson's disease (PD) and Type 2 Diabetes. Although preclinical studies have examined the effect of high-fat feeding on dopamine function in brain reward pathways, the effect of diet on neurotransmission in the nigrostriatal pathway, which is affected in PD and parkinsonism, is less clear. We hypothesized that a high-fat diet, which models early-stage Type 2 Diabetes, would disrupt nigrostriatal dopamine function in young adult Fischer 344 rats. Rats were fed a high fat diet (60% calories from fat) or a normal chow diet for 12 weeks. High fat-fed animals were insulin resistant compared to chow-fed controls. Potassium-evoked dopamine release and dopamine clearance were measured in the striatum using in vivo electrochemistry. Dopamine release was attenuated and dopamine clearance was diminished in the high-fat diet group compared to chow-fed rats. Magnetic resonance imaging indicated increased iron deposition in the substantia nigra of the high fat group. This finding was supported by alterations in the expression of several proteins involved in iron metabolism in the substantia nigra in this group compared to chow-fed animals. The diet-induced systemic and basal ganglia-specific changes may play a role in the observed impairment of nigrostriatal dopamine function.

P.1.009 Effects of the novel antiparkinsonian drug hemantane on brain bioelectric activity in mice with parkinsonian syndrome

A beam-walking apparatus has been evaluated for its ability to detect motor impairments in mice acutely treated with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg, s.c., single or double administration). Mice subjected to MPTP lesioning showed deficits in motor performance on the beam-walking task, for up to 6 days post-MPTP administration, as compared to saline-treated controls. In addition, MPTP-treated mice were detected to have a marked depletion in striatal dopamine levels and a concomitant reduction in substantia nigra (SN) tyrosine hydroxylase (TH) immunoreactivity, at 7 days post-MPTP administration, indicative of dopaminergic neuronal loss. Pre-administration of the potent MAO-B inhibitor R-(−)-deprenyl at 3 or 10 mg/kg, 30 min, s.c, significantly inhibited the MPTP-induced reduction in SN TH-immunoreactivity, striatal dopamine depletions and impairments in mouse motor function. The data described in the present study provides further evidence that functional deficits following an acute MPTP dosing schedule in mice can be quantified and are related to nigro-striatal dopamine function.

Functional neuroimaging in Parkinson's disease

Functional neuroimaging techniques have greatly contributed to improving our understanding of Parkinson's disease (PD) neurodegeneration and related compensatory mechanisms. In this paper, the authors analyze the role of functional neuroimaging as a diagnostic tool in PD and review functional neuroimaging studies on PD progression and compensatory adaptations. Through this, the article provides the reader with sensible approaches for the use of functional neuroimaging in the diagnosis of PD. The reader is also provided with knowledge on the time course of nigrostriatal dopamine dysfunction in PD as well as an overview of the potential beneficial and deleterious effects of increased dopamine turnover. Finally, the reader is provided with a critical discussion of the differential effects of levodopa and dopamine agonists on presynaptic dopamine markers and the implications for the interpretation of clinical trials. Functional neuroimaging probably plays a limited role in the diagnosis of PD. Parkinson's disease pathology leads to an exponential decline in nigrostriatal dopamine function and a compensatory increase in dopamine turnover, which may help delay symptom onset. On the negative side, increased dopamine turnover contributes to the development of treatment-related motor complications. Presynaptic markers of dopamine function are subject to regulatory changes, compromising the direct interpretation of neuroimaging results in trials of neuroprotective therapies for PD.

Advances in the Role of Neuroimaging to Monitor Disease Progression in Parkinson’s Disease

Since structural imaging has generally failed to demonstrate consistent abnormalities in Parkinson’s disease (PD), from an imaging perspective, the diagnosis has typically been based upon the demonstration of impaired striatal dopamine (DA) function. Radiotracer imaging techniques such as positron emission tomography (PET) and single photon emission computerized tomography (SPECT) allow thein vivoassessment of nigrostriatal DA function as well as regional cerebral blood flow, glucose metabolism, and functional connectivity, and changes in these measures have been used to infer disease progression. Pre-synaptic radiotracer imaging (RTI) has shown that striatal dopaminergic hypofunction follows a negative exponential pattern with the fastest rate of decline in early disease. Moreover, while striatal subregions remain differentially affected throughout the course of disease, with the posterior putamen affected more than anterior structures, the rate of deterioration is similar in all subregions. However, although functional imaging is undoubtedly a very useful tool in the assessment of PD progression, various studies have shown discordance between clinical progression of PD and nigrostriatal degeneration estimated by PET or SPECT. Therefore, considerable caution is warranted in the interpretation of imaging findings. While a potentially invaluable complement in assessing the severity of dopaminergic dysfunction, functional imaging is not a substitute for clinical assessment and other objective measures of PD severity, and cannot be currently considered a biomarker for progression of PD.

Advances in the Role of Neuroimaging to Monitor Disease Progression in Parkinson’s Disease

Since structural imaging has generally failed to demonstrate consistent abnormalities in Parkinson’s disease (PD), from an imaging perspective, the diagnosis has typically been based upon the demonstration of impaired striatal dopamine (DA) function. Radiotracer imaging techniques such as positron emission tomography (PET) and single photon emission computerised tomography (SPECT) allow thein vivoassessment of nigrostriatal DA function as well as regional cerebral blood flow, glucose metabolism, and functional connectivity, and changes in these measures have been used to infer disease progression. Pre-synaptic radiotracer imaging (RTI) has shown that striatal dopaminergic hypofunction follows a negative exponential pattern with the fastest rate of decline in early disease. Moreover, while striatal subregions remain differentially affected throughout the course of disease, with the posterior putamen affected more than anterior structures, the rate of deterioration is similar in all subregions. However, although functional imaging is undoubtedly a very useful tool in the assessment of PD progression, various studies have shown discordance between clinical progression of PD and nigrostriatal degeneration estimated by PET or SPECT. Therefore, considerable caution is warranted in the interpretation of imaging findings. While a potentially invaluable complement in assessing the severity of dopaminergic dysfunction, functional imaging is not a substitute for clinical assessment and other objective measures of PD severity, and cannot be currently considered a biomarker for progression of PD.

Ghrelin Promotes and Protects Nigrostriatal Dopamine Function via a UCP2-Dependent Mitochondrial Mechanism

Ghrelin targets the hypothalamus to regulate food intake and adiposity. Endogenous ghrelin receptors [growth hormone secretagogue receptor (GHSR)] are also present in extrahypothalamic sites where they promote circuit activity associated with learning and memory, and reward seeking behavior. Here, we show that the substantia nigra pars compacta (SNpc), a brain region where dopamine (DA) cell degeneration leads to Parkinson's disease (PD), expresses GHSR. Ghrelin binds to SNpc cells, electrically activates SNpc DA neurons, increases tyrosine hydroxylase mRNA and increases DA concentration in the dorsal striatum. Exogenous ghrelin administration decreased SNpc DA cell loss and restricted striatal dopamine loss after 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP) treatment. Genetic ablation of ghrelin or the ghrelin receptor (GHSR) increased SNpc DA cell loss and lowered striatal dopamine levels after MPTP treatment, an effect that was reversed by selective reactivation of GHSR in catecholaminergic neurons. Ghrelin-induced neuroprotection was dependent on the mitochondrial redox state via uncoupling protein 2 (UCP2)-dependent alterations in mitochondrial respiration, reactive oxygen species production, and biogenesis. Together, our data reveal that peripheral ghrelin plays an important role in the maintenance and protection of normal nigrostriatal dopamine function by activating UCP2-dependent mitochondrial mechanisms. These studies support ghrelin as a novel therapeutic strategy to combat neurodegeneration, loss of appetite and body weight associated with PD. Finally, we discuss the potential implications of these studies on the link between obesity and neurodegeneration.

99mTc-TRODAT-1 SPECT study in evaluation of Holmes tremor after thalamic hemorrhage

Holmes tremor is also known as rubral or midbrain tremor. The tremor usually involves lesions near the red nucleus and the nerve fiber tracts originating in the cerebellum and the substantia nigra. We report a case of a 62-year-old woman who presented with Holmes tremor 5 months after a left thalamic hemorrhage, with a partial recovery 3 years later. Sequential technetium-(99m)TRODAT-1 single-photon emission computed tomography (SPECT) of the patient's brain revealed partially improved tracer uptake reduction in the striatums, particularly on the left side. We propose that involvement of both the nigrostriatal and the dentate-rubro-thalamic pathways are essential in the pathogenesis of Holmes tremor after a thalamic lesion, and regeneration of the nigrostriatal system is possible in this type of tremor after the initial degeneration. The (99m)Tc-TRODAT-1 SPECT study is a useful and convenient tool for evaluating the nigrostriatal dopamine function in patients with Holmes tremor.

Compromised circadian function in Parkinson's disease: Enucleation augments disease severity in the unilateral model

Like enucleation, lateral hypothalamic (LH) lesions sever the connection between the retina and the pineal thereby simulating ambient exposure to constant darkness. While LH lesions have been employed to study either circadian function or Parkinson's disease (PD) independently, the application of such lesions to study circadian involvement specifically in this disease has never been attempted. In the present study, unilateral lesions of the LH, which compromise nigro-striatal dopamine (NSD) function, were combined with enucleation ipsilateral or contralateral to the hemisphere where 6-hydroxydopamine was applied. In addition to the observation that hemi-enucleation produced patterns of motor function that were grossly atypical compared to visually intact rats, hemi-enucleation ipsilateral to the side of NSD system denervation produced impairment of horizontal movement, limb retraction, ambulation and spontaneous or l-dopa induced turning. This impairment was more severe than that seen in rats with unilateral 6-OHDA lesions alone. Furthermore, hemi-enucleation contralateral to the side of unilateral NSD system denervation resulted in significantly improved performance on several parameters. While the rate of mortality in rats receiving unilateral 6-OHDA plus ipsilateral enucleation was similar to that occurring after bilateral lesions, it was not accompanied by severe weight loss and wasting that typically occurs in the acute stages of experimental PD. These results demonstrate the importance of the visual and circadian systems in PD and are consistent with reports that identify impaired circadian involvement as a major component in a wide range of neurological and neuropsychiatric conditions.

Intraocular microinjections repair experimental Parkinson's disease

Circadian involvement in Parkinson's disease (PD) and more specifically in nigro-striatal dopamine (NSD) function is of increasing interest to the neurosciences. Given that bright light therapy is of therapeutic value in PD, possible mechanisms underlying retinal involvement in this phenomenon was explored further by administering anti-Parkinsonian chemotherapies into the vitreus humour directly adjacent to the retina. 2 μl of a 100 mM solution of l-Dopa significantly improved motor function in the later stages of degeneration and during the day while the injection of 2 μl of a 10 mM solution of the melatonin receptor antagonist ML-23 improved motor function in the early stages of PD and during the dark phase of the light/dark cycle. The results suggest that the function of nigral cells is regulated by a more global system embracing circadian physiology that extends from the retina to the pineal. Furthermore, the induction of PD is characterised by an imbalance between melatonin and dopamine (DA) whereby this ratio is elevated at least 6 to 1 in favour of melatonin. The commonly observed treatment failures and side effects of DA replacement therapy probably result from increasing endogenous DA without taking parallel melatonin dysfunction into account. The proposed integrated function of the NSD and circadian systems may permit therapeutic targeting at a level which is safer, more effective and without the side effects of systemically administered regimens of DA replacement.

A beam-walking apparatus to assess behavioural impairments in MPTP-treated mice: Pharmacological validation with R-(−)-deprenyl

A beam-walking apparatus has been evaluated for its ability to detect motor impairments in mice acutely treated with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg, s.c., single or double administration). Mice subjected to MPTP lesioning showed deficits in motor performance on the beam-walking task, for up to 6 days post-MPTP administration, as compared to saline-treated controls. In addition, MPTP-treated mice were detected to have a marked depletion in striatal dopamine levels and a concomitant reduction in substantia nigra (SN) tyrosine hydroxylase (TH) immunoreactivity, at 7 days post-MPTP administration, indicative of dopaminergic neuronal loss. Pre-administration of the potent MAO-B inhibitor R-(−)-deprenyl at 3 or 10 mg/kg, 30 min, s.c, significantly inhibited the MPTP-induced reduction in SN TH-immunoreactivity, striatal dopamine depletions and impairments in mouse motor function. The data described in the present study provides further evidence that functional deficits following an acute MPTP dosing schedule in mice can be quantified and are related to nigro-striatal dopamine function.