Decrease In Dopamine Transporter Research Articles

Melatonin protects against methamphetamine-induced Alzheimer's disease-like pathological changes in rat hippocampus

Methamphetamine (METH) is a psychostimulant drug of abuse. METH use is associated with cognitive impairments and neurochemical abnormalities comparable to pathological changes observed in Alzheimer's disease (AD). These observations have stimulated the idea that METH abusers might be prone to develop AD-like signs and symptoms. Melatonin, the pineal hormone, is considered as a potential therapeutic intervention against AD. We thus conducted the present study to explore potential protective roles of melatonin against METH-induced deficits in learning and memory as well as in the appearance of AD-like pathological changes in METH-treated male Wistar rats. We found that melatonin ameliorated METH-induced cognitive impairments in those rats. Melatonin prevented METH-induced decrease in dopamine transporter (DAT) expression in rat hippocampus. Melatonin reversed METH-induced activation of β-arrestin2, reduction of phosphorylation of protein kinase B (Akt) and METH-induced excessive activity of glycogen synthase kinase-3β (GSK3β). Importantly, melatonin inhibited METH-induced changes in the expression of β-site APP cleaving enzyme (BACE1), disintegrin and metalloproteinase 10 (ADAM10), and presenilin 1 (PS1), as well as the reduction of amyloid beta (Aβ)42 production. Immunofluorescence double-labeling demonstrated that melatonin not only prevented the METH-induced loss of DAT but also prevented METH-induced Aβ42 overexpression in the dentate gyrus, CA1, and CA3. Furthermore, melatonin also suppressed METH-induced increase in phosphorylated tau. Significantly, melatonin attenuated METH-induced increase in N-methyl-D-aspartate receptor subtype 2 B (NR2B) protein expression and restored METH-induced reduction of Ca2+/calmodulin-dependent protein kinase II (CaMKII). This suggested that melatonin attenuated the toxic effect of METH on the hippocampus involving the amyloidogenic pathway. Taken together, our data suggest that METH abuse may be a predisposing risk factor for AD and that melatonin could serve as a potential therapeutic agent to prevent METH-induced AD like pathology.

Czy intensywny wysiłek fizyczny może być lekiem w chorobie Parkinsona?

Badania naukowe wskazują, że aktywność fizyczna wpływa nie tylko na polepszenie ogólnego stanu zdrowia u ludzi, ale dowodzą również specyficznego wpływu ćwiczeń fizycznych na "zdrowie mózgu". Doniesienia ostatnich lat pokazują, że uprawianie aktywności fizycznej w młodym wieku obniża ryzyko zachorowania na choroby neurodegeneracyjne, np. na chorobę Parkinsona. Jednocześnie istnieje wiele badań naukowych, prowadzonych na zwierzętach i ludziach wskazujących, że ćwiczenia fizyczne wywołują korzystne zmiany neuroplastyczne w mózgu zarówno u ludzi zdrowych jak i u chorujących na choroby neurodegeneracyjne. Niniejszy artykuł przedstawia dowody naukowe na zmiany neuroprotekcyjne i neuronaprawcze w mózgu wywołane ćwiczeniami fizycznymi. Zagadnieniem które szerzej podjęto w niniejszym artykule jest wpływ ćwiczeń fizycznych o wysokiej intensywności na zmiany neuroplastyczne i mechanizmy neurofizjologiczne ośrodkowego układu nerwowego oraz na zachowania psychomotoryczne w chorobie Parkinsona. Przedstawione w niniejszym artykule dowody naukowe na pozytywne efekty wysiłku fizycznego na ośrodkowy układ nerwowy to: (i) wzrost wydzielania czynników neurotroficznych, (ii) wzrost ekspresji receptorów dopaminergicznych D2 w prążkowiu, (iii) spadek aktywności transportera dopaminergicznego, (iv) wydłużenie korowo-rdzeniowego okresu ciszy u pacjentów z chorobą Parkinsona zbadanego za pomocą metody przezczaszkowej stymulacji magnetycznej, (v) poprawa sprawności czynności ruchowych oburęcznych, (vi) poprawa funkcji kognitywnych oraz (viii) złagodzenie symptomów ruchowych i pozaruchowych choroby Parkinsona. Wiedza ta jest ważna dla fizjoterapeutów poszukujących skutecznych metod terapii ruchem opartych na dowodach naukowych, wskazujących na wpływ odpowiednio dozowanego wysiłku na patomechanizm choroby Parkinsona, jak również dla modyfikacji systemu opieki zdrowotnej. Niniejszy artykuł ma również uświadomić każdemu z nas, jak wielki wpływ mamy na nasze "zdrowie mózgu" gdy regularnie uprawiamy aktywność fizyczną na każdym etapie naszego życia.

Ellagic Acid Prevents Dopamine Neuron Degeneration from Oxidative Stress and Neuroinflammation in MPTP Model of Parkinson's Disease.

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases and is characterized by progressive dopaminergic neurodegeneration in the substantia nigra pars compacta area. In the present study, treatment of EA for 1 week at a dose of 10 mg/kg body weight prior to MPTP (25 mg/kg body weight) was carried out. MPTP administration caused oxidative stress, as evidenced by decreased activities of superoxide dismutase and catalase, and the depletion of reduced glutathione with a concomitant rise in the lipid peroxidation product, malondialdehyde. It also significantly increased the pro-inflammatory cytokines and elevated the inflammatory mediators like cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in the striatum. Immunohistochemical analysis revealed a loss of dopamine neurons in the SNc area and a decrease in dopamine transporter in the striatum following MPTP administration. However, treatment with EA prior to MPTP injection significantly rescued the dopaminergic neurons and dopamine transporter. EA treatment further restored antioxidant enzymes, prevented the depletion of glutathione and inhibited lipid peroxidation, in addition to the attenuation of pro-inflammatory cytokines. EA also reduced the levels of COX-2 and iNOS. The findings of the present study demonstrate that EA protects against MPTP-induced PD and the observed neuroprotective effects can be attributed to its potent antioxidant and anti-inflammatory properties.

Psychosocial stress enhances susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity in C57BL/6N mice.

Psychological stress is thought to be a risk factor for the onset or accelerate the progression of Parkinson's disease. The main aim of this study is to explore the causative effect of confrontational housing (CH), a paradigm developed as an animal model of psychosocial stress, in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. When mice were housed confrontationally for 24 h, they displayed increased anxiety like-behavior in the light/dark box test. Administration of MPTP after CH for 24 h caused severe damage of striatal dopaminergic neurons as indicated by decreases in dopamine transporter and tyrosine hydroxylase proteins and an increase of glial fibrillary acidic protein levels compared to CH alone. The dose of MPTP used this study slightly affected these protein levels in the striatum of control mice, but they did not significantly change. Our results indicate that the striatal dopaminergic neurons are vulnerable to environmental risk factors that presumably have neurotoxin-like properties under psychological stress condition.

Altered dopamine release and monoamine transporters in Vps35 p.D620N knock-in mice

Vacuolar protein sorting 35 (VPS35) is a core component of the retromer trimer required for endosomal membrane-associated protein trafficking. The discovery of a missense mutation, Vps35 p.D620N implicates retromer dysfunction in the pathogenesis of Parkinson’s disease (PD). We have characterized a knock-in mouse with a Vps35 p.D620N substitution (hereafter referred to as VKI) at 3 months of age. Standardized behavioral testing did not observe overt movement disorder. Tyrosine hydroxylase (TH)-positive nigral neuron counts and terminal expression in striata were comparable across genotypes. Fast scan cyclic voltammetry revealed increased dopamine release in VKI striatal slices. While extracellular dopamine collected via striatal microdialysis of freely moving animals was comparable across genotypes, the ratio of dopamine metabolites to dopamine suggests increased dopamine turnover in VKI homozygous mice. Western blot of striatal proteins revealed a genotype-dependent decrease in dopamine transporter (DAT) along with an increase in vesicular monoamine transporter 2 (VMAT2), albeit independent of changes in other synaptic markers. The reduction in DAT was further supported by immunohistochemical analysis. The data show that the dopaminergic system of VKI mice is profoundly altered relative to wild-type littermates. We conclude early synaptic dysfunction contributes to age-related pathophysiology in the nigrostriatal system that may lead to parkinsonism in man.

A Pilot Study of F-18 FP-CIT PET Imaging in Early-onset Patients with Parkinson’s Disease: Parkin versus Non-parkin Mutation

Striatal dopaminergic dysfunction in early-onset Parkinson’s disease (PD) remains to be further elucidated. Thus, as a preliminary study, we aimed to investigate detailed patterns of dopaminergic depletion in five early-onset PD patients with dynamic N-(3-[(18) F]fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl) nortropane (FP-CIT) positron emission tomography (PET) scans. Two patients with parkin mutation showed more symmetric decrease of dopamine transporter (DAT) density in the putamen, whereas others displayed asymmetric reduction of DAT density in the putamen. Notably, only those with parkin mutation revealed more severe dopaminergic deficits in the anteroventral putamen rather than the posterodoral putamen. Our observation suggests, among PD patients, patients with parkin mutation may exhibit the different pattern of striatal dopaminergic depletion.

Decrease of dopamine transporter correlates cognitive decline in rapid eye movement behavior disorder patients

Decrease of dopamine transporter correlates cognitive decline in rapid eye movement behavior disorder patients

Acute Depletion of D2 Receptors from the Rat Substantia Nigra Alters Dopamine Kinetics in the Dorsal Striatum and Drug Responsivity.

Recent studies have used conditional knockout mice to selectively delete the D2 autoreceptor; however, these approaches result in global deletion of D2 autoreceptors early in development. The present study takes a different approach using RNA interference (RNAi) to knockdown the expression of the D2 receptors (D2R) in the substantia nigra (SN), including dopaminergic neurons, which project primarily to the dorsal striatum (dStr) in adult rats. This approach restricts the knockdown primarily to nigrostriatal pathways, leaving mesolimbic D2 autoreceptors intact. Analyses of dopamine (DA) kinetics in the dStr reveal a decrease in DA transporter (DAT) function in the knockdown rats, an effect not observed in D2 autoreceptor knockout mouse models. SN D2 knockdown rats exhibit a behavioral phenotype characterized by persistent enhancement of locomotor activity in a familiar open field, reduced locomotor responsiveness to high doses of cocaine and the ability to overcome haloperidol-induced immobility on the bar test. Together these results demonstrate that presynaptic D2R can be depleted from specific neuronal populations and implicates nigrostriatal D2R in different behavioral responses to psychotropic drugs.

The combination of ethanol with mephedrone increases the signs of neurotoxicity and impairs neurogenesis and learning in adolescent CD-1 mice

A new family of psychostimulants, under the name of cathinones, has broken into the market in the last decade. In light of the fact that around 95% of cathinone consumers have been reported to combine them with alcoholic drinks, we sought to study the consequences of the concomitant administration of ethanol on mephedrone ­induced neurotoxicity. Adolescent male Swiss­CD1 mice were administered four times in one day, every 2h, with saline, mephedrone (25mg/kg), ethanol (2; 1.5; 1.5; 1g/kg) and their combination at a room temperature of 26±2°C. The combination with ethanol impaired mephedrone­induced decreases in dopamine transporter and tyrosine hydroxylase in the frontal cortex; and in serotonin transporter and tryptophan hydroxylase in the hippocampus by approximately 2­fold, 7days post­treatment. Furthermore, these decreases correlated with a 2­fold increase in lipid peroxidation, measured as concentration of malondialdehyde (MDA), 24h post-treatment, and were accompanied by changes in oxidative stress-related enzymes. Ethanol also notably potentiated mephedrone-induced negative effects on learning and memory, as well as hippocampal neurogenesis, measured through the Morris water maze (MWM) and 5-bromo-2′-deoxyuridine staining, respectively. These results are of special significance, since alcohol is widely co­abused with amphetamine derivatives such as mephedrone, especially during adolescence, a crucial stage in brain maturation. Given that the hippocampus is greatly involved in learning and memory processes, normal brain development in young adults could be affected with permanent behavioral consequences after this type of drug co-abuse.

Effects of Jitai tablet, a traditional Chinese medicine, on spontaneous withdrawal symptoms and modulation of dopaminergic functions in morphine-dependent rats.

Chronic opioid abuse can cause damage to dopamine neurons. However, there are currently no effective pharmacotherapies to reverse this damage, even though progress has been made in the development of therapeutic strategies for opioid dependence. The Jitai tablet (JTT) is a traditional Chinese medicine formulation most commonly used for opioid addiction treatment in China. In a morphine spontaneous withdrawal rat model we investigated the effects of JTT, either given before (pre-treatment) or after (post-treatment) morphine administration, on the dopamine system. Our study has shown the following: (1) pre- and post-treatment with JTT were effective at alleviating the wet dog shakes and episodes of writhing; (2) pre-treatment with JTT inhibited the morphine-induced decreases in dopamine transporter (DAT), dopamine D2 receptor (D2 R) and tyrosine hydroxylase (TH) levels in the striatum (p < 0.01, compared with morphine group) and maintained them at normal levels; and (3) post-treatment with JTT restored the densities of DAT, D2 R and TH in the striatum to normal levels (p < 0.01, compared with morphine group). These results support the notion that modulation of the dopamine system in the striatum may play a role for JTT's therapeutic effect on the alleviation of opioid withdrawal symptoms.

Interactions of dopamine (DA) D2‐like receptor availability and DA transporters (DAT) on cocaine self‐administration in female cynomolgus monkeys

Using PET imaging, we recently reported that female monkeys who become dominant showed a significant increase in dopamine (DA) D2‐like receptor availability compared to subordinate animals who showed significant decreases in DA transporter (DAT) availability (Nader et al. 2012). In contrast to males, it appears that higher D2‐like availability was associated with greater vulnerability to cocaine reinforcement. However, it is possible that DAT availability was the more important vulnerability trait. The goal of this study was to further examine the role of D2‐like receptor and DAT availability on cocaine self‐administration (SA) in female cynomolgus monkeys (n=10). Individually housed female monkeys were scanned twice, once with the D2‐like receptor ligand [11C]raclopride and once with the DAT ligand [18F]FECNT. All monkeys were trained to respond under a multiple fixed‐interval 3‐min schedule of food and cocaine reinforcement. Food was available in components 1 and 3 and drug (or saline) in components 2 and 4. Although still preliminary, there appears to be no relationship between food‐maintained responding and DAT availability. Cocaine will be made available for SA and responding will be correlated with D2‐like and DAT availability. These studies will provide important information related to DA receptor function and vulnerability in a female monkey model of cocaine abuse. DA017763

Lesion of the cerebellar paravermis increases dopamine D1 receptor levels in the contralateral striatum

Anatomical and biochemical findings have long suggested that a projection from the cerebellum to the basal ganglia exists, and recent findings proposed that the cerebellum influences glutamatergic striatal activity. We have previously shown that a complete, genetic, lack of Purkinje cells induces an upregulation of dopamine D1 receptors (DRD1) in the output of the basal ganglia, the substantia nigra pars reticulata. In this study, we produced a focal unilateral lesion in the cerebellar paravermal cortex and we studied the levels and distribution of dopamine receptors and transporters, with the use of in vitro receptor autoradiography. The lesion produced a statistically significant increase in DRD1 specific binding in the contralateral medial striatum and a bilateral decrease in dopamine transporter (DAT) levels in the dorsolateral striatum. Our finding of a DRD1 increase after disruption of the cerebellar corticonuclear projection suggests that the cerebellar output modulates the basal ganglia DRD1-mediated pathway.

MPTP Animal Model of Parkinsonism: Dopamine Cell Death or Only Tyrosine Hydroxylase Impairment? – A Study Using PET Imaging, Autoradiography, and Immunohistochemistry in the Cat

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin widely used to produce experimental models of Parkinson's disease in laboratory animals. It is believed to cause a selective destruction of substantia nigra dopamine neurons, mainly based on a large reduction of tyrosine hydroxylase (TH), the catecholamine's synthesizing enzyme. Unlike Parkinson's disease in humans, however, all animal models are able to recover more or less rapidly from the MPTP induced Parkinsonian syndrome. This raises the question as whether MPTP causes a cell death with a decrease in dopamine transporter or a simple impairment of TH. To respond to this question, we quantified in a cat model of Parkinson's disease (MPTP 5mg/kg i.p. during 5days) the dopamine transporter using positron emission tomography (PET) imaging and autoradiography of [(11) C]PE2I and compared the data with the TH-immunoreactivity. We found no changes in [(11) C]PE2I PET binding either 5 or 26days after MPTP treatment when compared to baseline levels. Similarly, there were no significant changes in [(11) C]PE2I autoradiographic binding in the cat brain one week after MPTP treatment. In sharp contrast, MPTP treated cats exhibited severe Parkinson-like motor syndrome during the acute period with a marked decrease in TH-immunoreactivity in the striatum. These data suggest that MPTP toxicity impairs efficiently TH and that such an effect is not necessarily accompanied by significant reduction of dopamine transporter seen with in vitro or in vivo [(11) C]PE2I binding.

Oral administration of coenzyme Q10 reduces MPTP-induced loss of dopaminergic nerve terminals in the striatum in mice

The neuroprotective effect of coenzyme Q(10) (CoQ(10)) has been reported in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. In this study, we investigated whether oral administration of CoQ(10) could protect the striatal dopaminergic (DAergic) nerve terminals against MPTP-induced toxicity in C57BL/6N mice using immunoisolation technique for DAergic synaptosomes. CoQ(10) significantly attenuated decrease in dopamine transporter as well as in synaptophysin and actin protein levels in DAergic synaptosomes from MPTP-treated mice. The effect of CoQ(10) was also observed in crude synaptosomes fraction, but not in homogenate. Our results indicate that the nerve terminals are a site for the action of CoQ(10) against the MPTP-induced DAergic neurodegeneration.

Different striatal D 2-like receptor function in an early stage after unilateral striatal lesion and medial forebrain bundle lesion in rats

Unilateral striatal lesion and complete medial forebrain bundle (MFB) lesion by 6-hydroxydopamine in rats have been widely used as Parkinson disease (PD) models. However, the difference of pre- and post-synaptic dopamine (DA) system in these two models are not well concerned. In order to investigate the pathophysiologic difference between the MFB lesion rats and striatal lesion rats, we studied the variation of pre-synaptic DA transporter and post-synaptic D 2-like receptor in nigrostriatal DA system using binding assay, behavioral test and a small animal PET. Our data showed that there was a same tendency of the striatal DA transporter decrease both in MFB lesion rats and striatal lesion rats 4 weeks after lesion, however, it showed increase (up-regulation) of D 2-like receptor in the MFB lesion rats, whereas showed decrease (down-regulation) in the striatal lesion rat. This finding strongly indicated the different dynamic pathophysiologic process between the MFB lesion model and striatal lesion model. MFB lesion model mimics an early stage of PD, whereas striatal lesion model mimics Parkinson syndrome, such as vascular Parkinson syndrome. Such difference should be taken into account in the selection of these model systems.

Extended Methamphetamine Self-Administration in Rats Results in a Selective Reduction of Dopamine Transporter Levels in the Prefrontal Cortex and Dorsal Striatum Not Accompanied by Marked Monoaminergic Depletion

Chronic abuse of methamphetamine leads to cognitive dysfunction and high rates of relapse, paralleled by significant changes of brain dopamine and serotonin neurotransmission. Previously, we found that rats with extended access to methamphetamine self-administration displayed enhanced methamphetamine-primed reinstatement of drug-seeking and cognitive deficits relative to limited access animals. The present study investigated whether extended access to methamphetamine self-administration produced abnormalities in dopamine and serotonin systems in rat forebrain. Rats self-administered methamphetamine (0.02-mg/i.v. infusion) during daily 1-h sessions for 7 to 10 days, followed by either short- (1-h) or long-access (6-h) self-administration for 12 to 14 days. Lever responding was extinguished for 2 weeks before either reinstatement testing or rapid decapitation and tissue dissection. Tissue levels of monoamine transporters and markers of methamphetamine-induced toxicity were analyzed in several forebrain areas. Long-access methamphetamine self-administration resulted in escalation of daily drug intake ( approximately 7 mg/kg/day) and enhanced drug-primed reinstatement compared with the short-access group. Furthermore, long-, but not short-access to self-administered methamphetamine resulted in persistent decreases in dopamine transporter (DAT) protein levels in the prefrontal cortex and dorsal striatum. In contrast, only minor alterations in the tissue levels of dopamine or its metabolites were found, and no changes in markers specific for dopamine terminals or glial cell activation were detected. Our findings suggest that persistent methamphetamine seeking is associated with region-selective changes in DAT levels without accompanying monoaminergic neurotoxicity. Greater understanding of the neuroadaptations underlying persistent methamphetamine seeking and cognitive deficits could yield targets suitable for future therapeutic interventions.

Sustained depolarization decreases calcium/calmodulin-dependent protein kinase II activity and gene expression in dopamine neurons

Altered gene expression mediated by calcium/calmodulin-dependent protein kinase II (CaMKII) and other intracellular signaling molecules plays an important role in activity-dependent neuroplasticity. We discovered that sustained depolarization induced by KCl, a commonly used paradigm for studying activity-dependent gene expression, surprisingly caused a decrease in CaMKII activity in rat mesencephalic dopamine neurons. This decrease in CaMKII activity, after 2 days of depolarization, occurred in the presence of a continued elevation in intracellular calcium concentration. An increase in calyculin-sensitive phosphatase activity was at least partly responsible for the decrease in CaMKII activity. Phosphatase assays revealed that activity but not the abundance of protein phosphatase-2A was increased by sustained depolarization. Decreased CaMKII activity was accompanied by a selective decrease in dopamine transporter (DAT) mRNA, while tyrosine hydroxylase and actin mRNA abundance was unaltered. On the other hand, brain-derived neurotrophic factor (BDNF) mRNA abundance was increased by sustained depolarization, further demonstrating the specificity of changes. Depolarization also caused a significant decrease in DAT protein abundance and DAT-mediated uptake. Taken together, these data illustrate a novel signaling paradigm in which the activity of protein phosphatase-2A is associated with CaMKII activity and gene expression.

Environmental enrichment decreases cell surface expression of the dopamine transporter in rat medial prefrontal cortex

Rats raised in an enriched environmental condition (EC) exhibit a decreased (35%) maximal velocity (V(max)) of [3H]dopamine (DA) uptake in medial prefrontal cortex (mPFC) compared with rats raised in an impoverished condition (IC); however, no differences between EC and IC groups in V(max) for [3H]DA uptake were found in nucleus accumbens and striatum. Using biotinylation and immunoblotting techniques, the present study examined whether the brain region-specific decrease in DA transporter (DAT) function is the result of a reduction in DAT cell surface expression. In mPFC, nucleus accumbens and striatum, total DAT immunoreactivity was not different between EC and IC groups. Whereas no differences in cell surface expression of DAT were found in nucleus accumbens and striatum, DAT immunoreactivity in the biotinylated cell surface fraction of mPFC was decreased (39%) in EC compared with IC rats, consistent with the magnitude of the previously observed decrease in V(max) for [3H]DA uptake in mPFC in EC rats. These results suggest that the decrease in DAT cell surface expression in the mPFC may be responsible for decreased DAT function in the mPFC of EC compared with IC rats, and that there is plasticity in the regulatory mechanisms mediating DAT trafficking and function.

Relationship among nigrostriatal denervation, parkinsonism, and dyskinesias in the MPTP primate model

Presynaptic denervation is likely to play an important role in the pathophysiology of dyskinesias that develop after levodopa administration to patients with Parkinson's disease. In this study, the thresholds of nigrostriatal damage necessary for the occurrence of parkinsonism and levodopa-induced involuntary movements were compared in squirrel monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Animals treated with a regimen of MPTP that caused parkinsonism displayed > or =95% striatal dopamine depletion, 90% reduction of striatal dopamine uptake sites, and 70% nigral neuronal loss. Levodopa administration ameliorated the parkinsonian signs of these monkeys but also induced dyskinesias. A separate group of animals was treated with a milder MPTP regimen that caused 60%-70% striatal dopamine depletion, a 50% decrease in dopamine transporter, and 40% loss of dopaminergic nigral neurons. While these monkeys displayed no behavioral signs of parkinsonism, they all became dyskinetic after levodopa administration. The priming effect of levodopa, that is, the recurrence of dyskinesias in animals previously exposed to the drug, was compared in severely versus mildly lesioned monkeys. When severely injured parkinsonian animals underwent a second cycle of levodopa treatment, they immediately and consistently developed involuntary movements. In contrast, the recurrence of dyskinesias in primed monkeys with a partial nigrostriatal lesion required several levodopa administrations and remained relatively sporadic. The data indicate that moderate nigrostriatal damage which does not induce clinical parkinsonism predisposes to levodopa-induced dyskinesias. Once dyskinesias have been induced, the severity of denervation may enhance the sensitivity to subsequent levodopa exposures.

Comparison between the decrease of dopamine transporter and that of L‐DOPA uptake for detection of early to advanced stage of Parkinson's disease in animal models

Early diagnosis of Parkinson's disease (PD) is important for the potential application of neuroprotective therapies. The purpose of this study was to assess the detection of the early changes of PD by either imaging the dopamine transporter (DAT) or uptake of l-3,4-dihydroxyphenylalanine (l-DOPA). An early to advanced stage model of PD was induced in rats by stereotaxic injection of 1–10 μg 6-hydroxydopamine (6-OHDA) into the substantia nigra pars compacta. Using adjacent sections of the same animals, the binding of [I-125]beta-CIT, which labels DAT and the uptake of [C-14]l-DOPA, were evaluated 4 weeks after induction of the lesion. Any decrease in dopaminergic neurons was evaluated by in situ hybridization histochemistry (ISH) by detection of DAT mRNA-positive neurons. In addition, the expression levels of DAT, dopa decarboxylase (DDC), and vesicular monoamine transporter (VMAT2) in each neuron were studied with ISH. Our results show a decrease in both [I-125]beta-CIT binding and [C-14]l-DOPA uptake in parallel with a decrease in DA neurons from early to advanced stage models of PD. The decrease in [C-14]l-DOPA uptake was smaller than that in [I-125]beta-CIT binding in the same animal (P < 0.0001). Expression levels of DAT, DDC, and VMAT2 mRNAs were also decreased with the progression of the disease. Although ISH failed to detect the origin of the discrepancy between [I-125]beta-CIT and [C-14]l-DOPA levels, it was concluded that [C-14]l-DOPA levels underestimated the decrease of dopaminergic neurons and that [I-125]beta-CIT levels more precisely reflected the decrease. Synapse 31:178–185, 1999. © 1999 Wiley-Liss, Inc.