1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) enhances tryptophan hydroxylase activity in mouse striatum, but not in the frontal cortex

We measured serotonin (5-HT) and 5-hydroxyindole-3-acetic acid (5-HIAA) contents and tryptophan hydroxylase (TPH) activity in mouse striatum and frontal cortex after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment (7 daily injections of 30 mg/kg). In the striatum, TPH activity was increased for at least 4 weeks after injection of MPTP, along with an increase in 5-HIAA. However, no significant change was observed in 5-HT, 5-HIAA or TPH activity in the frontal cortex. These results suggest that MPTP affects 5-HT through a change in TPH activity, specifically at nerve terminals in the striatum.     

Neuropathological study on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine of the crab-eating monkey

Summary Experimental parkinsonism was induced by systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the crab-eating monkey (Macaca fascicularis). In the acute stage, the substantia nigra showed necrotic nerve cells, extracellular release of pigment granules and histiocytic infiltration. The nerve cells underwent vacuolation of the cytoplasm with chromatin clumping of the nucleus and disintegration of the nucleolus. The striking feature was the presence of variously-shaped inclusion bodies within abnormal mitochondria which sometimes disclosed a distortion of the cristae. Golgi apparatus and endoplasmic reticulum were also dilated. In the locus ceruleus swollen nerve cells were observed with vacuolated cytoplasm and pyknotic nucleus where expanded mitochondria also contained the inclusions. Some of the inclusion bodies are probably insoluble precipitations due to inhibition of mitochondrial oxidation by a certain metabolite of MPTP. In the protracted stage the substantia nigra revealed a considerable loss of the nerve cells associated with melanophagia and astrocytic proliferation. A few surviving nerve cells showed an increased number of Golgi apparatus and rough endoplasmic reticula, and the presence of autophagosomes, dense bodies and intra-mitochondrial inclusions. These changes are interpreted as being a part of the reparative process from the cellular damage.Supported in part by a grant from CNS Degeneration Disease Research Committee, the Ministry of Health and Welfare of Japan     

Expression of c-Jun in dopaminergic neurons of the substantia nigra in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice

The expression of c-Jun in the brains of young (8-week-old) and older (52-week-old) mice following administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was investigated immunocytochemically. Both age groups exhibited reduction in the number of dopaminergic neurons in the substantia nigra after administration of MPTP. There was a significant difference in the magnitude of decrease in the number of dopaminergic neurons between the two groups, as has previously been reported, and the older mice exhibited more extensive loss of dopaminergic neurons in the substantia nigra after MPTP administration than did the young mice. Prolonged c-Jun expression was induced in the substantia nigra following administration of MPTP, and this induction was more prominent in the older mice than in the young mice. Maximum expression of c-Jun occurred on day 7 after the administration of MPTP in both groups. Double staining for tyrosine hydroxylase (TH; a dopaminergic neuron marker) and c-Jun revealed their co-localization indicating that the cells expressing c-Jun were dopaminergic neurons. Cytoplasmic volumes of strongly c-Jun positive cells were reduced, suggesting that they may have been degenerating. In situ end labeling revealed no apoptotic neurons after MPTP administration. These results suggest the existence of some cascade mechanism of nonapoptotic death of dopaminergic neurons following administration of MPTP.     

Drug-induced dyskinesia in primates rendered hemiparkinsonian by intracarotid administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

The right common carotid artery was surgically exposed under general anaesthesia in 6 cynomolgus monkeys and MPTP (0.5–2.2 mg/kg) directly infused. This produced a hemiparkinsonian syndrome in the contralateral limbs which responded to treatment with both levodopa and apomorphine. these drugs also precipitated dose-dependent contralateral rotation which reached a peak 2 weeks after MPTP infusion. A massive depletion of large, presumably dopaminergic cells was found from the ipsilateral substantia nigra pars compacta. Three animals receiving chronic therapy with apomorphine developed choreoathetoid movements of the limbs and the face contralateral to the infusion 2 weeks after the commencement of treatment. The severity of the dyskinesia gradually increased and after 4 weeks peak-dose hemiballistic movements were seen. Levodopa and the selective D-2 and D-1 dopamine agonists LY-171555 and SKF 38393 also reversed parkinsonian features and produced contralateral rotation and peak-dose dyskinesia. This unilateral model of parkinsonism in the primate will be of value in the elucidation of the mechanisms by which chronic levodopa or dopamine agonist therapy enhance involuntary movements in parkinsonism.     

Transplacentally-transported 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) affects the catecholamine and indoleamine levels in the fetal mouse brain

Summary The effects of a dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the amounts of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were examined in the whole brains of fetal mice and maternal mice after its administration to pregnant mice. DA and DOPAC concentrations were decreased significantly in both the fetal and maternal brains. At 3 hr after injection, reduction of the DOPAC concentration was more marked than that of DA in both the fetal and maternal brains. Increase of 5-HT concentration was observed until 12 hr after injection in the fetal brains and 6 hr in the maternal brains. These results indicate that 1-methyl-4-phenyl-pyridinium ion (MPP⁺) and MPTP affect the levels of catechol- and indoleamines in the brain of premature stage as well as in the mature brain.     

Morphological, neurochemical, and behavioral characterizations associated with the combined treatment of diethyldithiocarbamate and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice

Changes in striatal dopamine (DA) neurochemistry, tyrosine hydroxylase immunocytochemistry of DA fibers, and behavior following the combined administration of diethyldithiocarbamate (DDC) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mice were assessed. The combined treatment of DDC and MPTP produced a dose-dependent decrease in striatal DA levels and a dose-related increase in the striatal DOPAC:DA ratio. Cumulative doses of MPTP equal to or exceeding 53.0 (26.5 mg/kg x 2. i.p.), given in combination with DDC, were effective in reducing striatal DA levels to less than 25% of control levels 2 weeks after treatment. Tyrosine hydroxylase immunocytochemistry revealed large deafferentation of DA terminal regions in striatum, moderate reductions in nucleus accumbens and dendritic regions of substantia nigra, and slight reductions in the number of DA cell bodies in substantia nigra. Mice treated with DDC and MPTP became hyperactive during the light phase of their diurnal cycle: psychopharmacological data suggest that postsynaptic DA receptors were supersensitized following this treatment. These data provide evidence that the combined treatment of DDC and MPTP produces severe and enduring depletion of mesostriatal DA, and also concomitant behavioral changes in mice.     

Transplacental effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on brain dopaminergic neurons in the mouse

Summary Immunohistochemical studies of monoamme neurons werè performed to evaluate toxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on young adult mice and compare them with chose of their offspring. Mice, 9–11 weeks old (C57BL/6J), injected subcutaneously with a large dose of MPTP (17 mg/kg per day) during pregnancy on Day 9 and 12 of gestation (G9 and G12) miscarried and were examined at 13 weeks of age. Conversely, mice treated during pregnancy with sequential low dose of MPTP (2.8 mg/kg per day at G9–G17 for 8 days) successfully delivered their babies and were examined at the age of 15 weeks. Baby mice were examined at 1 and 6 weeks of age. The tyrosine hydroxylase-, aromatic l-amino acid decarboxylase-and dopamine (DA)-immunoreactive density of caudoputamen was reduced in 13-week-old mice treated with high dose of MPTP but not in the 15-week-old mothers exposed to a low dose of MPTP as compared to their respective controls. The DA-immunoreactive density of the caudoputamen was the only staining that was reduced in both 1- and 6-week-old baby mice. In conclusion, these results demonstrate that MPTP injected to pregnant mice causes a DA depletion in the striatum of their offspring indicating a transplacental effect of MPTP. The findings also indicate that fetal brain is more susceptible to MPTP toxicity than the brain of young pregnant mice.Supported by Grant-in-Aid for Scientific Research on Priority Areas, Ministry of Education, Science and Culture, Japan (62623002, 62480226), and by a Fujita-Gakuen Health University Grant, Japan     

Disappearance of circadian rhythms in Parkinson''s disease model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in dogs

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to dogs produces clinical, pathological and neurological features in dog resembling human Parkinson's disease. Using this animal model, we studied the changes in diurnal rhythms of urine volume, creatinine in urine, and vasopressin, aldosterone and renin activity in plasma. Before MPTP treatment, urine volume showed a peak between 17.00 and 1.00 and plasma vasopressin concentration also showed a clear circadian rhythm with a peak at 13.00 and a minimum level at 5.00. Two weeks after MPTP treatment (2.5 mg/kg i.v.), the rhythm of urine volume disappeared and that of vasopressin became less clear. Plasma renin activity increased 2 and 4 weeks after MPTP treatment. The increase was, however, not enough to change the concentration of plasma aldosterone. We examined the effect of L-3,4-dihydroxyphenylalanine (levodopa), on the circadian pattern of urine volume and vasopressin attenuated by MPTP. Levodopa (4 mg/kg/day) was administered orally every day from the first week after MPTP treatment. The circadian rhythms of urine volume and vasopressin reappeared within one week after the start of levodopa administration.     

Neurochemical changes in the substantiae nigrae and caudate nuclei following acute unilateral intranigral infusions of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Acute unilateral intranigral infusions of MPTP at doses (200 micrograms) which produce robust contralateral rotation in the rat induced significant neurochemical changes in the ipsilateral as well as contralateral nigrostriatal systems. There were pronounced increases in the levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the ipsilateral substantia nigra and a significant decrease in the levels of DA in the ipsilateral caudate nucleus while opposite changes occurred in the contralateral substantia nigra and caudate nucleus. The DOPAC:DA and HVA:DA ratios were significantly higher in the ipsilateral caudate nucleus indicating increased activity of the ipsilateral nigrostriatal DA neurones. The levels of noradrenaline and 4-hydroxy-3-methoxyphenylethyline glycol (MHPG) increased and decreased significantly in the ipsilateral and contralateral substantia nigra, respectively, but there were no significant changes in the caudate nuclei. The levels of serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) increased significantly in the ipsilateral substantia nigra and caudate nucleus as well as in the contralateral caudate nucleus but did not increase significantly in the contralateral substantia nigra. The 5-HIAA:5-HT ratio was significantly decreased in the contralateral caudate nucleus indicating a reduced activity of the contralateral nigrostriatal 5-HT neurones. The data thus indicate that MPTP applied to one substantia nigra is capable of producing profound neurochemical changes not only locally but also in the ipsilateral striatum as well as in the contralateral nigrostriatal system. Previous neuropharmacological studies have suggested that the rotation induced by intranigral MPTP may be mediated via dopamine released from dendrites in the pars reticulata in response to MPTP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential protein expression in substantia nigra induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine in a mouse model of chronic Parkinson''''s disease

BACKGROUND: To date, a complete protein expression profile of the midbrain substantia nigra in a mouse model of chronic Parkinson's disease, induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), does not exist. In addition, there are no reports of analysis of differential protein expression.OBJECTIVE: To separate and evaluate MPTP-induced differential protein expression through the use of proteomics in the substantia nigra of a mouse model of chronic Parkinson's disease.DESIGN: Randomized controlled animal study.SETTING: Department of Neurology, the First Affiliated Hospital, Chongqing Medical University.MATERIALS: Sixteen 8-10-week old, healthy, male, C57BL mice, weighing 20-25g, and of clean grade, were provided by the Experimental Animal Center of Chongqing Medical University. The experimental animals were disposed according to ethical criteria. MPTP was provided by Sigma Company, USA; Pdquest 2D image analysis software and gelatum/irradiance image analysis system (ChemiDoc XRS) by Bio-Rad, USA; and Voyager DE-PROMALDI-TOF-MS mass spectroscopy analyzer by ABI Company, USA.METHODS: This study was performed in Chongqing Neurological Laboratory between November 2006 and July 2007. Mice were randomly divided into model and control groups, with 8 mice in each group. Mice in the model group were Received a subcutaneous injection of MPTP (25mg/kg), twice a week, for five successive weeks, to establish a chronic Parkinson's disease model. Mice in the control group 收稿日期 the same volume of a subcutaneous saline injection at the same time points. Mice were sacrificed by anesthesia to rapidly obtain the midbrain for protein separation of the substantia nigra.MAIN OUTCOME MEASURES: (1) 2-ED handbook (Bio-Rad Company) was referenced for two-dimensional electrophoresis. (2) PDQUEST8.0 analytical electrophoresis pattern was adopted to evaluate differential protein expression. (3) Peptide mass finger print map and data were retrieved on http://www.prospector.ucsf.edu to compare differential substantia nigral protein expression in the two groups.RESULTS: Two-dimensional gel electrophoresis of substantia nigra tissue indicated that there were 33 differential protein expressions between the two groups. Three new proteins were evaluated, including α-enolase, which exhibited regulated expression, tumor necrosis factor ligand superfamily member 4, and cyclin-dependent kinase inhibitor 1B.CONCLUSION: There are three proteins that exhibit differential expression in the substantia nigra-α-enolase, tumor necrosis factor ligand superfamily member 4, and cyclin-dependent kinase inhibitor 1B.     

The effect of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on uridine uptake in the mouse brain

Male white mice were injected with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 40 mg/kg. After 2 h, 24 h, 2, 4 and 8 days 0.25 mCi [5-3H]uridine was injected i.v. and 1 h later the animals were sacrificed. In microautoradiograms the number of grains over the nerve cell nuclei was counted in the substantia nigra, the cerebral cortex, the hippocampus and the neostriatum. In the substantia nigra there was a significant increase in grain number after 2, 4 and 8 days. In a group of animals injected 3 days with MPTP and sacrificed 2 days after the last injection the same increase was found. In the other brain regions only an insignificant increase in grain counts was found. In a special group of animals the total radioactivity and distribution of label on metabolites in blood, brain and liver was determined. No significant changes were found.     

Decreases in mouse brain NAD and ATP induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): prevention by the poly(ADP-ribose) polymerase inhibitor, benzamide

Inhibitors of poly(ADP-ribose) polymerase (PARP), including benzamide, protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine neurotoxicity in vivo [Cosi et al., Brain Res. 729 (1996) 264–269]. In vitro, the activation of PARP by free radical damaged DNA has been shown to be correlated with rapid decreases in the cellular levels of its substrate nicotinamide adenine dinucleotide (NAD⁺), and ATP. Here, we investigated in vivo whether MPTP acutely caused region- and time-dependent changes in brain levels of NAD⁺, ATP, ADP and AMP in C57BL/6N mice killed by head-focused microwave irradiation, and whether such effects were modified by treatments with neuroprotective doses of benzamide. At 1 h after MPTP injections (4×20 mg/kg i.p.), NAD⁺ was reduced by 11–13% in the striatum and ventral midbrain, but not in the frontal cortex. The ATP/ADP ratio was reduced by 10% and 32% in the striatum and cortex, respectively, but was unchanged in the midbrain. All of these regional changes were prevented by co-treatment with benzamide (2×160 mg/kg i.p.), which by itself did not alter regional levels of NAD⁺, ATP, ADP or AMP in control mice. In a time-course study, a single dose of MPTP (30 mg/kg i.p.) resulted in maximal and transient increases in striatal levels of MPP⁺ and 3-methoxytyramine (+540%) at 0.5–2 h, followed by maximal and coincidental decreases in NAD⁺ (−10%), ATP (−11%) and dopamine content (−39%) at 3 h. Benzamide (1×640 mg/kg i.p., 30 min before MPTP) partially reduced MPP⁺ levels by 30% with little or no effect on MPTP or MPDP⁺ levels, did not affect or even slightly potentiated the increase in 3-methoxytyramine, and completely prevented the losses in striatal NAD⁺, ATP and dopamine content, without by itself causing any changes in these latter parameters in control mice. These results (1) confirm that MPTP reduces striatal ATP levels [Chan et al., J. Neurochem. 57 (1991) 348–351.]; (2) show that MPTP causes a regionally-dependent (striatal and midbrain) loss of NAD⁺; (3) indicate that the PARP inhibitor benzamide can prevent these losses without interfering with MPTP-induced striatal dopamine release; and (4) provide further evidence to suggest an involvement of PARP in MPTP-induced neurotoxicity in vivo.     

Pharmacological effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on striatal dopamine receptor system

In mice, chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces an increase in the maximum number of [³H]spiperone binding sites in the striatum. The sensitivity of striatal protein phosphorylation to calcium plus calmodulin is also potentiated in MPTP-treated mice. These observations are associated with an enhancement of apomorphine-induced climbing behavior in the drug-treated animals. The results of this study suggest that in an animal model for Parkinson's disease, MPTP interrupts the dopamine (DA) transmission by chemically denervating the nigrostriatal neurons and through a compensatory mechanism, it increases the number of DA receptors as well as the sensitivity of protein phosphorylation to calcium plus calmodulin in mouse striatum. The latter two events may contribute to the development of DA receptor supersensitivity.     

Neurotoxic effects of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the cat. Tyrosine hydroxylase immunohistochemistry

N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces substantia nigra pars compacta (SNc) cell death in several species including the mouse, dog and monkey. MPTP is presently shown to cause apparent nigral cell death in the SNc of the cat as noted by a long-lasting decrease in tyrosine-hydroxylase (TH)-like cell staining. A transient loss of TH-like staining is also observed in the ventral tegmental area, locus coeruleus and retrorubral area. These latter areas appear normal 1.5-5.0 months after MPTP administration. The caudate nucleus (CD) showed a greater TH depletion than the nucleus accumbens (ACC) and only recovered slightly over time. After 7 days of MPTP, an apparent axonopathy, characterized by lightly staining fibers with large TH-positive varicosities, is seen in the CD and to a lesser extent, in the ACC. These findings demonstrate that MPTP is toxic to the cat's nigrostriatal dopaminergic system and suggests that the cat is a good intermediate species in which to study the responses of dopaminergic neurons to MPTP.     

Effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in goldfish cerebellum: neurochemical and immunocytochemical analysis

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administered in goldfish for 3 consecutive days (10 mg kg⁻¹ i.p.), caused cerebellar disappearance of dopamine-hydroxylase (DBH) immunoreactive fibres, whereas the noradrenergic cell bodies located in the medulla oblongata appeared intact. This effect was coupled with marked decreases in cerebellar noradrenaline (NA) and dopamine (DA) levels. An increase of immunostaining for glial fibrillary acidic protein (GFAP) was also observed. In the cerebellum of MPTP-treated fish, the contents of glutamate and GABA were significantly reduced, whereas glutamine was strongly increased. These modifications were concomitant with a significant increase of glutamine synthetase (GS) activity, whereas glutamic acid decarboxylase (GAD) activity was decreased. No changes in choline acetyltransferase (ChAT) and ornithine decarboxylase (ODC) activities were observed. High affinity uptake of glutamate and GABA was strongly reduced. Pretreatment of fish with either the monoamine oxidase inhibitor pargyline or the catecholamine (CA) uptake blocker mazindol largely prevented such modifications. The NMDA-sensitive glutamate receptor uncompetitive antagonist, dizocilpine maleate (MK-801), failed to protect against MPTP-induced damage. In conclusion, the neurotoxic effects of MPTP in goldfish cerebellum appear to be not specific against catecholaminergic terminals and could promote astrocytic reactions.     

Changes in the local cerebral metabolic rate for glucose in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of Parkinson''s disease

Nine adult monkeys (Macaca fascicularis) were used in this study. Five animals were used as controls. Three animals were injected intravenously daily with 0.5 mg/kg of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) over a 4-day period; one animal was injected weekly over a 4-week period. Neurological examination of the MPTP-treated animals revealed a flexed posture of trunk and extremities, bradykinesia, increased tone without cogwheel rigidity, loss of vestibular righting reflexes, decreased vocalization and swallowing, failure of upgaze and abnormal pursuit eye movements. Reflexes were hyperactive. The compound 2-deoxy-D-[14C]glucose (2-DG) was utilized for the determination of the local cerebral metabolic rate for glucose (lCMRg). A generalized decrease in lCMRg was noted in all cerebral cortical areas as compared to control values. The cerebellar cortex demonstrated no change in lCMRg. Areas that demonstrated a significant increase in lCMRg were: the internal and external segments of the globus pallidus (P less than 0.01), the pars compacta and the pars reticulata of the substantia nigra (P less than 0.05). Areas that demonstrated a significant decrease in lCMRg were: the head of the caudate nucleus (P less than 0.05), the anterior dorsomedial putamen (P less than 0.05) and the anterior segment of the subthalamic nucleus (P less than 0.05). The 2-DG analysis of the MPTP primate model of Parkinson's disease is particularly suited to demonstrate areas in the central nervous system that are affected by this neurotoxin. Further studies of these areas may lead to a better understanding of the mechanisms that underlie the clinical symptomatology of Parkinson's disease.     

Inhibition of tyrosine hydroxylation in tissue slices of the rat striatum by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a nigrostriatal neurotoxin in humans and primates, at 10⁻⁵ M inhibited hydroxylation of tyrosine to 3,4-dihydrophenylalanine (DOPA), the rate-limiting step of dopamine synthesis, in tissue slices of the striatum and nucleus accumbens of the rat. Nomifensine, an inhibitor of dopamine uptake, reversed the inhibition but sulpiride, a dopamine receptor antagonist, did not affect the inhibition. MPTP at 10⁻⁵ M inhibited neither the purified tyrosine hydroxylase nor dihydropteridine reductase in vitro. The level of total biopterin did not change significantly, but the tetrahydrobiopterin level was decreased in the striatal slices incubated in the presence of MPTP. These results suggest that MPTP inhibits dopamine synthesis in situ at the tyrosine hydroxylase step probably through inhibition of dihydropteridine reductase.     

Unilateral pallidotomy in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets exhibiting levodopa-induced dyskinesia

Pallidotomy paradoxically reduces the intensity of levodopa-induced dyskinesia without worsening motor symptoms. The reasons for this are not clear and no experimental study has investigated this phenomenon. The objective of this investigation was to evaluate the effects of unilateral pallidotomy on locomotor activity, motor disability and levodopa-induced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated levodopa-primed common marmosets. Animals were primed to exhibit dyskinesia by daily administration of levodopa until stable dyskinesia was evoked by each dose. Locomotor activity, motor disability and dyskinesia were assessed weekly at baseline and following an acute levodopa challenge. Prior to pallidotomies, two distinct groups of animals emerged: poor responders to levodopa with mild dyskinesia (Group 1) and those exhibiting a marked increase in motor activity and pronounced dyskinesia (Group 2). Electrolytic lesions were placed in the left internal segment of the globus pallidus. Pallidotomy had no effect on basal or levodopa-induced motor activity in either group but significantly improved basal motor disability in Group 2. Following pallidotomy, the ability of levodopa to reduce motor disability was significantly increased in both groups. Pallidotomy improved dyskinesia in both Groups 1 and 2 but it was more effective in reducing dystonia compared with chorea. The effect of pallidotomy on dyskinesia in Group 2 was transient, with the intensity of involuntary movements reverting to presurgery levels 4 weeks later. This study shows that in levodopa-primed, parkinsonian marmosets, placement of discrete globus pallidus lesions can ameliorate levodopa-induced dyskinesia but not akinesia. This model allows the evaluation of pallidotomy-induced biochemical changes in dyskinetic primates.     

Lithium and valproate prevent olfactory discrimination and short-term memory impairments in the intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rat model of Parkinson's disease

We have recently demonstrated that rodents treated intranasally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) display time-dependent impairments in olfactory, emotional, cognitive and motor functions associated with disruption of dopaminergic neurotransmission in different brain structures conceivably analogous to those observed during different stages of Parkinson's disease (PD). On the other hand, lithium (Li) and valproate (VPA) are two primary drugs used to treat bipolar mood disorder that have recently emerged as promising neuroprotective agents. The present data indicates that the pretreatment with Li (47.5 mg/kg) or VPA (200 mg/kg) by intraperitoneal route during 7 consecutive days was able to prevent olfactory discrimination and short-term memory impairments evaluated in the social recognition and step-down inhibitory avoidance tasks in rats infused with a single intranasal (i.n.) administration of MPTP (0.1 mg/nostril). Despite the absence of clear depressive-like responses following the current MPTP dose, Li and VPA treatment presented an antidepressant profile reducing the immobility time in the forced swimming test. Importantly, at this time no significant alterations on the locomotor activity of the animals were observed in the open field test. Moreover, Li and VPA prevented dopamine depletion in the olfactory bulb and striatum of MPTP-infused rats. These results provide new insights in experimental models of PD, indicating that Li and VPA may represent new therapeutic tools for the management of olfactory and cognitive symptoms associated to early preclinical phases of PD, together with their neuroprotective potential demonstrated in previous research.     

Dopamine-releasing action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridine (MPP) in the neostriatum of the rat as demonstrated in vivo by the push-pull perfusion technique: dependence on sodium but not calcium ions

This study examined the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its metabolite, 1-methyl-4-phenylpyridine (MPP+) on the levels of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in push-pull perfusates of the striatum in chloral hydrate-anaesthetized rats. In control animals the levels of DA and DOPAC remained stable for at least 6 h and responded rapidly to a depolarizing stimulus of 25 mM K+. This K+-induced DA release was Ca2+-dependent since no stimulation was observed when the striatal sites were perfused with high K+ in a Ca2+-free medium containing 2 mM EGTA thus verifying that the striatal sites were functionally active. MPTP (0.025 and 0.05 microgram/microliter) stimulated DA release and inhibited DOPAC output in a dose-related manner. MPP+ (0.01, 0.025 and 0.05 microgram/microliter) produced a more robust dose-dependent increase in DA levels in the perfusates; however, the level of suppression of DOPAC was similar to that in response to MPTP. The effect of MPP+ on DA release was attenuated by 10(-6) M benztropine, the DA re-uptake blocker and completely inhibited by 10 micrograms/kg i.p. benztropine and 10(-4) M ouabain, the Na+, K+-ATPase (Na pump) inhibitor. However, although these substances prevented the MPP+-induced release of DA, the levels of DOPAC in the perfusates did not recover and remained completely suppressed suggesting that MPP+ may inhibit extraneuronal rather than intraneuronal monoamine oxidase (MAO). Perfusion of the striatal sites with a Ca2+-free medium containing 2 mM EGTA did not prevent the MPP+-induced DA release indicating that MPP+ does not release DA from the striatal DA terminals by the Ca2+-dependent process of exocytosis. The responses of DA and DOPAC to 25 mM K+ were markedly suppressed in animals treated with MPTP and MPP+, these effects being most severe with the highest dose of MPP+. Moreover, this suppression of the K+-induced responses persisted in animals perfused with MPP+ in the presence of benztropine or ouabain, thus suggesting that MPP+ may have potent deleterious membrane effects. These studies have provided the first direct in vivo demonstration of the action of MPTP and MPP+ and the neuropharmacological basis of this action on DA metabolism in the rat striatum. The results show that the elevated levels of DA in the striatal perfusates are due to a direct action of MPTP and MPP+ on the nigrostriatal DA terminals and cannot be fully accounted for solely by their inhibition of MAO activity and/or inhibition of DA re-uptake.(ABSTRACT TRUNCATED AT 250 WORDS)