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PubMed2000

The protective effects of PBN against MPTP toxicity are independent of hydroxyl radical trapping.

To study the mechanism of the protective effect of the spin-trapping agent alpha-phenyl-N-tert-butyl nitrone (PBN) against MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) toxicity hydroxyl radicals and functional parameters of neuroprotection were determined. C57BL/6 mice received PBN (100 mg/kg IP) over a time period of 15 days and on day 8 MPTP (40 mg/kg SC). On day 15 striatal levels of dopamine, serotonin, and metabolites were analyzed. For radical determination mice received a single injection of salicylic acid (SA) (100 mg/kg IP) in the time period of 0.5 h before to 72 h after MPTP injection. In vivo maximum hydroxyl radical levels indicated by 2,3-dihydroxybenzoic acid/SA ratios were obtained 4 h after MPTP injection, and were not affected by PBN treatment. However, the MPTP-induced mortality, reduction of locomotor activity, continuous loss of body weight, and striatal dopamine depletion were significantly less pronounced in PBN-treated animals. These results elucidate the time course of hydroxyl free radical formation in MPTP toxicity. PBN improved the functional parameters of neuroprotection against MPTP toxicity, but there is no evidence for hydroxyl radical scavenging properties to this effect.

Animals↗
PubMed1997

Species differences in the role of excitatory amino acids in experimental parkinsonism.

The present review discusses species differences in relation to the effects produced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); in particular, it focuses on recent evidence regarding the role of excitatory amino acids in experimental parkinsonism. The main aim of the review is to provide a phylogenetic perspective which may serve as a useful tool to study Parkinson's disease in rodents. Excitotoxicity might represent the final common pathway on which the actions of different neurotoxins, selectively directed towards nigrostriatal dompaminergic neurons, converge. This is clearly demonstrated in methamphetamine- and 6-dihydroxy-dopamine-induced parkinsonism. The role of excitotoxicity in the mechanism of action of MPTP is less clear. Although there are several species differences for MPTP it is possible to obtain in mice the same effects induced in MPTP-treated primates by combining acetaldehyde or diethyldithiocarbamate with MPTP administration. When mice are administered these combined treatments, the onset of experimental parkinsonism can be prevented using the same pharmacological agents (i.e. glutamate N-methyl-D-aspartate antagonists) that are effective in primates.

Animals↗
PubMed2003

Effect of manganese exposure on MPTP neurotoxicities.

We used a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice model to evaluate whether manganese (Mn) exposure can affect MPTP-induced neurotoxicity. We randomly assigned adult male C57BL/6 mice (n=5-7 per group) the following treatments: SO, Mn(-) x MPTP(-); MO, Mn(+) x MPTP(-); SM, Mn(-) x MPTP(+); MM, Mn(+) x MPTP(+). Mn (MnCl(2).4H(2)O) was administered intraperitoneally at a dose of 2 mg/kg daily for 3 weeks. MPTP was then administered intraperitoneally at a dose of 30 mg/kg daily for 5 days in the SM and MM groups. Seven days after the last MPTP injection, the animals were sacrificed. Blood Mn levels were elevated in the Mn-exposed groups. Striatal Mn levels were not influenced by Mn treatment alone, however, they were decreased following MPTP. Tyrosine hydroxylase (TH)-immunoreactive (ir) neurons in the substantia nigra pars compacta (SNpc) were decreased significantly in the MPTP-exposed groups. Densities of TH- and dopamine transporter (DAT)-ir axon terminals in the caudate-putamen (CPU) were also decreased in the MPTP-treated groups. Furthermore, glial fibrillary acidic protein (GFAP)-ir astrocytes increased in the CPU with MPTP treatment. However, no effects were observed with Mn exposure. Concentrations of dopamine (DA), 3,4-dihydrophenyl acetic acid (DOPAC) and homovanillic acid (HVA) in the corpus striatum were also decreased significantly with MPTP treatment alone, but Mn had no effect. Thus, decreased dopaminergic activities with MPTP led to decreased DA and its metabolites. Significant hypertrophies of GFAP-ir astrocytes in the globus pallidus (GP) were observed in Mn-exposed groups, especially in the MM group. MPTP targeted dopaminergic systems whereas Mn neurotoxicities occurred in the GP. In conclusion, our data suggest that Mn does not potentiate the neurotoxicity of MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

Microglial and astrocytic involvement in a murine model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

We have studied the reaction of glial cells in mice treated with an intraperitoneal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a selective neurotoxin of dopaminergic nigrostriatal neurons. Signs of injury to the dopaminergic neurons started on the 1st day after MPTP administration and progressed up to the end of the observation time (21st day). A transient microglial reaction was demonstrated from the 1st until the 14th day in the substantia nigra (SN) and striatum. The cells showed an increase in number and changes in morphology. At the ultrastructural level, signs of phagocytosis and features indicating the secretion of biologically active substances were observed. Astrocytosis followed the microglial reaction by one day and was noticed until the end of the observation time. Interleukin-6 immunoreactivity was observed within microglia and astrocytes in the SN on days 2 and 3. There were no signs of depletion of dopaminergic cells or glial activation after the administration of MPTP simultaneously with pargyline, an inhibitor of monoamine oxidase-B that prevents MPTP neurotoxicity. Our study indicates that microglia and astrocytes are involved in the pathological process in the nigrostriatal system following MPTP administration. MPTP alone is not responsible for glial cell activation but its metabolite MPP+ and/or agents released by injured neurons may participate in this process.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2003

The establishment of a reliable cytotoxic system with SK-N-SH neuroblastoma cell culture.

A reliable in vitro cytotoxic system is essential in neurocytotoxic and neuroprotective research. The present study examined four cytotoxic insults with the SK-N-SH human neuroblastoma cell line. These were beta-amyloid protein (Abeta), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), high density culture, and serum deprivation induced neuronal death. These insults induced significant reduction in cell numbers after 96 h culture, in a concentration dependent manner. Among all the insults, MPTP, serum deprivation, and high density culture induced apoptosis after 96 h, while Abeta presumably induced necrotic neuronal death since apoptosis was not detectable. The p38 MAP kinase inhibitor, SB203580 (1 microM), and the PKC inhibitor, chelerythrine (5 microM) successfully inhibited the loss in viability caused by Abeta and the high density culture, respectively. Other kinase inhibitors, including the non-specific protein kinase inhibitor, H7, the PKA inhibitor 14-22 Amide, the PKG inhibitor, KT5823, and the protein tyrosine kinase inhibitor, AG18 had no effect on any of the four cytotoxic models. This system allows the study of neuroprotection under conditions where the different pathways and mechanisms of the neurons can be considered within one cellular system, removing variations which may be due to different cell type studied. The present studies describe an effective model system for screening potential neuroprotective agents.

Amyloid beta-Peptides↗
PubMed2003

Grid performance test to measure behavioral impairment in the MPTP-treated-mouse model of parkinsonism.

Behavioral impairments in mice following administration of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) require large depletions in striatal dopamine content and are often transient. In this paper, we describe a simple and inexpensive test that measures long-term behavioral deficits in mice treated with moderate doses of MPTP. These measures are significantly correlated with the loss of striatal dopamine and immunoreactivity of the dopamine transporter, vesicular monoamine transporter and tyrosine hydroxylase. In addition, behavioral impairments on the measures were reversed following L-DOPA administration. Employment of this test will allow for more efficacious use of mice in PD research, as well as provide more sensitive measures of behavioral improvement following potential therapeutic or neuroprotective interventions.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2000

Comparison of eight clinical rating scales used for the assessment of MPTP-induced parkinsonism in the Macaque monkey.

The most valuable model of Parkinson's disease available at present is the primate model treated with 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), frequently used to study response to new drugs or surgical treatments. The evaluation of such therapies requires clinical rating scales which measure precisely motor behaviour in both normal and parkinsonian monkeys. It is obvious that such evaluation can only be valid if parallel studies are carried out under similar experimental conditions with well-defined objective criteria. Hence the need to compare and assess the different rating scales in use if we want to be able to compare the results of clinical studies. In order to give rise to some fresh thinking on the necessity of a certain uniformity of assessment, this study compares eight clinical rating scales and considers their capacity to express in quantitative terms both the severity of MPTP intoxication in five cynomolgus monkeys and the alleviation afforded by levodopa. None of the eight scales reaches all the criteria despite the Kurlan scale would appear as an interesting working basis for a further consensual definition of a worldwide used parkinsonian monkey clinical rating scale

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2001

Profound astrogenesis in the striatum of adult mice following nigrostriatal dopaminergic lesion by repeated MPTP administration.

Neural progenitor cells are present in the rodent brain throughout adulthood, and can proliferate and differentiate into new neurons and/or glia to repair injury. To explore the repair processes mediated by brain progenitor cells, a selective lesion of the nigrostriatal dopaminergic pathway was induced in young adult mice by repeated administration of the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). A thymidine analog, bromodeoxyuridine (BrdU), was used as a tracer for DNA synthesis to label the dividing cells and their terminal progeny following injury. Three days after MPTP treatments (25 mg/kg, once daily for 5 days), an 8-fold increase in the number of BrdU-labeled newborn cells was observed in the dorsal striatum. A 5-fold increase was also seen in the substantia nigra (SN). Newborn cells in the striatum survived beyond 60 days after their birth whereas newborn cells in the SN survived for less than 31 days. The vast majority of newborn cells in the striatum differentiated into astroglia according to their radial morphology and co-expression with an astroglial marker, S100beta, within 10 days after birth. In contrast, most BrdU-positive cells in the SN failed to co-express S100beta. Little or none of BrdU-labeled cells in both the striatum and SN were found to co-localize with a neuronal marker, neuronal nuclear antigen, or tyrosine hydroxylase during the full course of survival days surveyed (3 to 60 days). Repeated MPTP also decreased dopamine content and uptake in the striatum, which showed a significant recovery 31 days after MPTP lesion. These results demonstrate a rapid and profound astrogenesis in the striatum of young adult mice in response to toxic dopaminergic insult. The lack of neurogenesis in the two affected brain areas indicates the relative importance of glial cell regeneration in repairing MPTP injury.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2001

Lymphocyte populations in Parkinson's disease and in rat models of parkinsonism.

To assess the involvement of the immune system in Parkinson's disease we studied the phenotype of circulating lymphocytes in 30 untreated and 34 treated patients. We found a numeric decrease in helper T cells (higher in CD4(+)CD45RA(+) than in CD4(+)CD29(+)) and B cells, and a rise in activated, CD4(+)CD25(+) lymphocytes that was correlated with lymphocyte depletion. All these alterations were independent of levodopa treatment. In addition, we performed striatal dopamine depletion in rats with either MPP(+) or 6-OHDA, showing that MPP(+) but not 6-OHDA can increase CD4(+)CD25(+) lymphocytes. Thus, mechanisms other than dopamine deficit may explain the immune activation in Parkinson's disease.

Aged↗
PubMed2003

Effect of postnatal iron administration on MPTP-induced behavioral deficits and neurotoxicity: behavioral enhancement by L-Dopa-MK-801 co-administration.

Two experiments were performed to investigate the interactive effects of postnatal iron administration and adult MPTP treatment upon the function of C57 Bl/6 mice tested at adult age and to ascertain the possible ameliatory effects of a subthreshold dose of L-Dopa co-administered with different doses of the uncompetitive glutamate antagonist, MK-801. Experiment I indicated that postnatal iron induced marked deficits (hypoactivity), initially, in all three parameters of motor activity at the 5.0 and 7.5 mg/kg doses, and to a lesser extent at the 2.5 mg/kg dose. Later combination with MPTP (2x40 mg/kg) potentiated severely these deficits. During the final period of testing a marked hyperactivity was obtained for the two higher dose groups; this effect was abolished in mice administered MPTP. Experiment II indicated that the deficits in motor activity parameters induced by postnatal iron at 7.5 mg/kg were alleviated in a dose-related manner by the co-administration of the uncompetitive glutamate antagonist, MK-801, with a subthreshold dose of L-Dopa. Postnatal iron (7.5 mg/kg) administration followed by low doses of MPTP (2x20 mg/kg) 3 months later virtually abolished all motor activity. The combination of these compounds increased also the motor activity of mice treated with MPTP (2x20 mg/kg) or mice treated with the combination of postnatal iron and MPTP. The combination of MK-801 with L-Dopa increased locomotor (0.3 mg/kg), rearing (0.1 and 0.3 mg/kg) and total activity (0.3 mg/kg) of iron-treated mice during the initial, hypoactive 30-min period of testing. Locomotor activity (0.1 mg/kg) of MPTP-treated mice was increased too during this period. During the final 30-min period of testing all three parameters of activity (locomotion, 0.3 mg/kg; rearing and total activity, 0.1 and 0.3 mg/kg) were enhanced in the iron-treated mice, locomotion (0.1 mg/kg) and rearing (0.1 mg/kg) in the iron plus MPTP treated mice and only locomotion (0.1 mg/kg) in the MPTP-treated mice. In control mice (vehicle+saline), the higher doses of MK-801 (0.1 and 0.3 mg/kg) enhanced both locomotor and total activity. Analyses of total iron concentration in the frontal cortex and basal ganglia of Fe(2+) and vehicle treated mice indicated that marked elevations basal ganglia iron levels of the 5.0 and 7.5 mg/kg groups, later injected either saline or MPTP, were obtained (Experiment I). In Experiment II, iron concentrations in the basal ganglia were elevated in both the Fe(2+)-sal and Fe(2+)-MPTP groups to 170 and 177% of Veh.-sal values, respectively. There was a significant increase in the frontal cortex of iron-treated mice later administered either saline or MPTP (2x40 mg/kg) in Experiment I as well as in those given iron followed by MPTP (2x20mg/kg) in Experiment II. The implications of iron overload in parkinsonism seem confirmed by the interactive effects of postnatal administration of the metal followed by adult MPTP treatment upon motor activity and the activity-enhancing effects of co-administration of L-Dopa with MK-801.

Animals↗
PubMed1996

Effects of L-DOPA-therapy on dopamine D2 receptor mRNA expression in the striatum of MPTP-intoxicated parkinsonian monkeys.

The cellular expression of dopamine D2 receptor mRNA was examined in striatal (caudate nucleus and putamen) neurones of 9 Macaca fascicularis monkeys rendered parkinsonian by systemic injection of MPTP. Messenger RNA abundance was determined by quantitative in situ hybridization using human-specific 35S-labelled oligonucleotides. Control monkeys were untreated and received neither MPTP nor L-DOPA while the rest were rendered parkinsonian and received chronic levodopa therapy to induce dyskinesia. In the control brains a strong dopamine D2 receptor hybridization signal was detected overlying medium-sized and some large neurons in both the caudate nucleus and putamen. Neurons from the lateral and medial regions of the caudate nucleus, and from the dorsal and ventral regions of the putamen were analysed separately. A significant increase in the cellular abundance of dopamine D2 receptor mRNA was seen in the striatum of MPTP-treated monkeys; this increase being restricted to the population of medium-sized striatal cells. No such increase in dopamine D2 receptor mRNA was observed in (dyskinetic) L-DOPA-treated monkeys suggesting that levodopa-therapy normalises D2 receptor expression in post-synaptic striatal cells. The cellular abundance of dopamine D2 receptor mRNA expressed by large striatal neurons (putative cholinergic cells) was unaffected by either MPTP treatment or levodopa therapy. The implications of these findings for the development of levodopa-induced dyskinesias is discussed.

Animals↗
PubMed1997

Elevated expression of glutathione peroxidase in PC12 cells results in protection against methamphetamine but not MPTP toxicity.

In vivo administration of either 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or methamphetamine (MA) produces damage to the dopaminergic nervous system which may be due in part to the generation of reactive oxygen species (ROS). The resistance of superoxide dismutase (SOD) over-expressing transgenic mice to the effects of both MPTP and MA suggests the involvement of superoxide in the resulting neurotoxicity of both compounds. Superoxide can be converted by SOD to hydrogen peroxide, which itself can cause cellular degeneration by reacting with free iron to produce highly reactive hydroxyl radicals resulting in damage to proteins, nucleic acids and membrane phospholipids. Hydrogen peroxide has also been reported to be produced via inhibition of NADH dehydrogenase by MPP + formed during oxidation of MPTP by MAO-B and by dopamine auto-oxidation following MA-induced dopamine release from synaptic vesicles within nerve terminals. To test whether hydrogen peroxide is an important factor in the toxicity of either of these two neurotoxins, we created clonal PC12 lines expressing elevated levels of the hydrogen peroxide-reducing enzyme glutathione peroxidase (GSHPx). Elevation of GSHPx levels in PC12 was found to diminish the rise in ROS levels and lipid peroxidation resulting from MA but not MPTP treatment. Elevated levels of GSHPx also appeared to prevent decreases in transport-mediated dopamine uptake produced via MA administration as well as to attenuate toxin-induced cell loss as measured by either MTT reduction or LDH release. Our data, therefore, suggest that hydrogen peroxide production likely contributes to MA toxicity in dopaminergic neurons.

Animals↗
PubMed1998

MPTP-Parkinsonism is accompanied by persistent expression of a delta-FosB-like protein in dopaminergic pathways.

Parkinson's disease (PD) is characterized by the relatively selective and progressive loss of dopaminergic neurons in the substantia nigra. During the early stages of PD, there are marked compensatory changes in the dopaminergic system, although little is known of how these responses are orchestrated. Since the induction of cellular immediate-early genes (cIEG) has been linked to adaptive responses in the nervous system, we examined their expression in the N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of PD. MPTP elicited an induction of c-fos, fosB, Delta-fosB and c-jun mRNAs in the striatum that persisted for 24 h. There was a parallel increase in AP-1-like DNA binding activity for up to 7 days post-treatment. At 7 days, AP-1 complexes were specifically supershifted with antisera to FosB and JunD. Immunoblotting of MPTP-treated striata with a FosB-specific antiserum revealed elevated levels of approximately 35 and approximately 46 kDa cross-reactive proteins. Only the 35 kDa protein was increased at 7 days. Thus, the persistent AP-1 complex seen in the MPTP-treated striatum is composed of JunD and a 35 kDa FosB-related protein, possibly Delta-FosB. In situ hybridization revealed elevated expression of fosB and Delta-fosB in the MPTP-treated brain. Expression of both transcripts was highest in ventral striatum, nucleus accumbens and other terminal fields of the mesolimbic system, such as the olfactory tubercle and Islands of Calleja. Thus, the increased fosB expression accompanying MPTP treatment was predominantly associated with dopaminergic pathways. Since FosB was expressed in both vulnerable and spared neuronal populations, we suggest that Delta-FosB-JunD heterodimers play a role in the adaptive response to MPTP neurotoxicity.

Aging↗
PubMed1999

Lactoferrin is synthesized by mouse brain tissue and its expression is enhanced after MPTP treatment.

The presence of iron in brain tissue in increased concentrations in Parkinson's disease cases, where it might be responsible for oxidative stress, and the parallel observation that the iron transporter lactoferrin (Lf) was present in increased amounts in surviving neurons, led us to study the synthesis of Lf in a mouse model of Parkinson's disease. In this context, the origin and expression of brain Lf in normal, aged and MPTP (1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine)-treated mice were investigated. Lf immunostaining was observed mainly on microvessels in the cerebral cortex of the adult mice and to a greater extent in older mice. Lf immunoreactivity was also present in the hippocampus only in the aged mouse brains, associated with structures which seemed to be pyramidal neurons and fibers. After RT-PCR (polymerase chain reaction), Lf transcripts were found in mouse brain tissue whatever the age of the animals studied but the level of their expression was very low. No up-regulation of Lf was detectable during aging. Lf distribution and expression in the MPTP-induced Parkinsonian mouse model were also investigated. A marked depletion of dopamine (DA) occurred in the high dose MPTP-treated mice. The level of Lf expression was found to be markedly increased in the same animals and this up-regulation occurred on the first day after MPTP administration. When the brain was stressed by the neurotoxin MPTP, Lf expression increased in line with antioxidant enzymes such as catalase and gamma-glutamylcysteine synthetase, which may permit the protection of brain tissue from oxidative damage induced by the drug.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1999

Cocaine reward and MPTP toxicity: alteration by regional variant dopamine transporter overexpression.

Polygenic factors play important roles in animal models of substance abuse and susceptibility to dopaminergic neurodegeneration. Genetic factors are also likely to contribute to the etiology of human drug abuse disorders, and may alter human vulnerabilities to Parkinsonian neurodegeneration. The dopamine transporter (DAT; SLC6A3) is densely expressed by the dopaminergic midbrain neurons that play central roles in drug reward and is believed to be a primary site of action for cocaine reward. This transporter is necessary for the action of selective dopaminergic neurotoxins, and is uniquely expressed on neurons that are the primary targets of Parkinsonian neurodegeneration. To study possible influences of variant DAT expression on these processes, we have constructed transgenic mice (THDAT) in which tyrosine hydroxylase (TH) promoter sequences drive expression of a rat DAT cDNA variant, increase striatal DAT expression by 20-30%, and provide modest alterations in striatal levels of dopamine and its metabolites. THDAT mice habituate more rapidly to a novel environment than wildtype littermates. These animals display enhanced reward conferred by cocaine, as measured by conditioned place preference. However, locomotor responses to cocaine administration are similar to those of wildtype mice, except at high cocaine doses. THDAT mice display more than 50% greater losses of dopaminergic neurons following a course of MPTP treatment than do wildtype control mice. These results document a model for allelic variation at a gene locus that can exert significant effects in murine models of human substance abuse vulnerability and dopaminergic neurodegeneration.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

Protection against MPTP treatment by an analog of Pro-Leu-Gly-NH2 (PLG, MIF-1)

3(R)-[(2(S)-Pyrrolidinyl-carbonyl)amino]-2-oxo-1-pyrrolidineacetamide (PAOPA) is a peptidomimetic analog of Pro-Leu-Gly-NH2 (PLG or MIF-1) that has previously been demonstrated to be more potent and efficacious that MIF-1 in enhancing dopamine receptor activity. Given the ability of MIF-1 to protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioning in C57 BL/6 mice, the present study was undertaken to evaluate the neuroprotective effect of PAOPA in this model. PAOPA was found to be more potent and efficacious that MIF-1 in sparing dopamine and its metabolite levels following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. Whether the enhanced neuroprotective effect of PAOPA is due to dopamine receptor stimulation, or a result of reduced oxidative stress through normalization of dopamine turnover, remains to be determined.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1999

Alteration of neurotensin receptors in MPTP-treated mice.

We examined the sequential changes in neurotensin receptors in the striatum and substantia nigra of mouse brains lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by receptor autoradiography, in comparison with the alterations in dopamine uptake sites. The mice received four intraperitoneal injections of MPTP (10 mg/kg) at 1-h intervals and then the brains were analyzed at 6 h and 1, 3, 7, and 21 days after the treatments. [3H]Neurotensin and [3H]mazindol were used to label neurotensin receptors and dopamine uptake sites, respectively. [3H]Neurotensin binding was significantly decreased in the striatum from 6 h to 21 days after MPTP treatment. In the substantia nigra, pars reticulata also showed a significant decrease in [3H]neurotensin binding from 3 to 21 days post-MPTP treatment. However, no significant change in [3H]neurotensin binding was observed in the pars compacta even after 21 days. On the other hand, [3H]mazindol binding was markedly decreased in the striatum and substantia nigra from 6 h to 21 days after MPTP treatment. These results indicate that neurotoxin MPTP can produce a severe decrease in neurotensin receptors and dopamine uptake sites in the striatum and substantia nigra of mice. Thus, our findings provide evidence that the dysfunction in neurotensin receptors may be involved in the degenerative processes causing Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗