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PubMed1997

Talipexole or pramipexole combinations with chloro-APB (SKF 82958) in MPTP-induced hemiparkinsonian monkeys.

The effects of two predominant dopamine D2-like receptor agonists, talipexole (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d]-azepine dihydrochloride, B-HT 920 CL2) and pramipexole (S(-)2-amino-4,5,6,7-tetrahydro-6-propyl-aminobenzothiazole dihydrochloride, SND 919 CL2Y), were studied alone and in combination with the selective dopamine D1-like receptor agonist chloro-APB ((+/-)6-chloro-7-8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-benz azepine hydrobromide, SKF 82958) in five chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned hemiparkinsonian Macaca nemestrina monkeys. Talipexole induced contraversive rotation in a dose-dependent manner up to 32 microg/kg, i.m. Talipexole was more potent than pramipexole (10 vs. 32 microg/kg, i.m.), but pramipexole was more efficacious in producing contraversive rotational behavior and significant hand movements in the afflicted limb. Larger doses of chloro-APB also produced contraversive rotation. Combinations of each dopamine D2-like receptor agonist in a median effective dose with chloro-APB (23.4 and 74.8 microg/kg, i.m.) had synergistic effects, producing either addition or potentiation, depending upon the dose used. The effects noted with these combinations were less than the effect of a large dose (100 microg/kg) of pramipexole. Talipexole, in the largest dose studied (100 microg/kg, i.m.), produced sedation which was not seen with the same dose of pramipexole. No significant extrapyramidal side effects were noted with either agent.

Animals↗
PubMed1998

Differences in pre- and post-synaptic sensitivity to apomorphine between saline and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated C57BL/6 mice as reflected in climbing activity.

The climbing behaviour after low doses (0.05, 0.1 and 0.2 mg/kg) or a high dose (1.5 mg/kg) of apomorphine was studied in saline or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57BL/6 mice. Following a 3-week recovery from two injections of saline or MPTP (50 mg/kg inter-injection period: 72 h), mice were randomly selected for determinations of contents of neurotransmitters and metabolites (dopamine, homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindole-3-acetic acid (5-HIAA)) or the apomorphine-induced climbing paradigm. For the climbing experiment, the animals were habituated for 60 min to metal climbing cylinders after which they received a subcutaneous injection of apomorphine or its solvent. Subsequently, the animals were placed back in the cylinders and their climbing scores were recorded every 5 min for 60 min. The biochemical data indicated that striatal levels of dopamine, DOPAC and HVA were significantly reduced following MPTP-treatment whereas striatal 5-HT and 5-HIAA levels were unaffected. In the climbing paradigm saline and MPTP-treated C57BL/6 mice responded diametrically opposite to low doses of apomorphine: 0.1 and 0.2 mg/kg apomorphine reduced the climbing score in saline-treated mice as compared to saline injections whereas 0.2 mg/kg apomorphine increased the climbing score in MPTP-treated mice. A relatively high dose of apomorphine (1.5 mg/kg) increased the climbing score in both saline- and MPTP-treated mice. However, the climbing score was significantly higher in MPTP-treated mice than in saline-treated mice. These data suggest that MPTP-treated mice lack pre-synaptic dopamine receptors and have an increased post-synaptic sensitivity for apomorphine which is in agreement with the fact that MPTP selectively affects the dopaminergic nigro-striatal pathway which then results in an up-regulation of post-synaptic receptors.

Animals↗
PubMed1998

Parallel modulation of striatal dopamine synthetic enzymes by second messenger pathways.

The activity of tyrosine hydroxylase and aromatic L-amino acid decarboxylase in the striatum and their mRNA content in the midbrain were assayed in mice following the intracerebroventricular injection of forskolin or phorbol-12,13-myristic acid (PMA). Control and 1-methyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned animals were studied. Both forskolin and PMA induced a rapid and transient increase of tyrosine hydroxylase and aromatic L-amino acid decarboxylase activity in the striatum that lasted less than 45 and 60 min, respectively. A second belated increase of striatal tyrosine hydroxylase and aromatic L-amino acid decarboxylase activities was seen only after forskolin, and it was accompanied by a rise of tyrosine hydroxylase and aromatic L-amino acid decarboxylase mRNA in the midbrain. In the MPTP-lesioned mouse, the rise of tyrosine hydroxylase and aromatic L-amino acid decarboxylase following forskolin appeared exaggerated, while the response to PMA was not. These studies suggest that tyrosine hydroxylase and aromatic L-amino acid decarboxylase of striatum can be modulated in parallel by protein kinase A and protein kinase C, and that exaggerated responsiveness to protein kinase A is observed in the partially denervated striatum.

Animals↗
PubMed1989

Different sensitivities to MPTP toxicity in primate nigrostriatal and retinal dopaminergic systems: electrophysiological and biochemical evidence.

The influences of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on dopamine content in the retina and the striatum of monkeys, as well as retinal responses to flash stimulation were studied. Dopamine depletion was observed in the striatum, while retinal dopamine content was similar to controls. The electroretinograms and the oscillatory potentials remained normal, even in monkeys presenting a severe Parkinsonian syndrome, in concordance with the biochemical data. It is proposed that the retinal dopaminergic system is less sensitive to the toxic effects of MPTP than the nigro-striatal pathway.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2003

Microglial response is poorly correlated with neurodegeneration following chronic, low-dose MPTP administration in monkeys.

Many investigators have reported extensive microglial activation in the mouse substantia nigra and striatum following acute, high-dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. Our previous work demonstrated tyrosine hydroxylase (TH)-positive fiber sprouting in the striatum in monkeys that had received a partial dopaminergic lesion using a low-dose, chronic MPTP administration paradigm. To characterize the microglial response, we utilized HLA-DR (LN3) to immunolabel the class II major histocompatibility complex (MHC II). In MPTP-treated monkeys, there was an intense microglial response in the substantia nigra, nigrostriatal tract, and in both segments of the globus pallidus. This response was morphologically heterogeneous, with commingled ramified, activated, and multicellular morphologies throughout the extent of these basal ganglia structures. Surprisingly, there was little evidence of microglial reactivity in the striatum despite evidence of neurodegeneration-by silver labeling and by loss of TH immunolabeling. Moreover, this pattern of microglial reactivity was the same in all animals that had received MPTP and seemed to be independent of the degree of neurotoxin-induced neurodegeneration. Thus, we conclude that microglial reactivity, per se, is not consistently associated with neurodegeneration, but depends on regional differences.

Animals↗
PubMed1997

Melatonin is protective against MPTP-induced striatal and hippocampal lesions.

The in vivo effect of melatonin on MPTP-induced neurotoxicity in mouse brain was studied. Melatonin (10 mg/kg) or saline was administered intraperitoneally (i.p.) to mice 30 min prior to a s.c. injection of MPTP (20 mg/kg). After MPTP treatment, the animals received melatonin or saline injections every hour for three hours. Mice were killed 4 hours after the MPTP injection. Regionally-specific increases in lipid peroxidation were observed in corpus striatum and hippocampus (71% and 58%, respectively), but not in cerebral cortex, cerebellum or midbrain. Treatment with melatonin completely reversed the rises in lipid peroxidation products. MPTP-treated mice showed a significant decrease in the striatal tyrosine hydroxylase immunoreactive nerve terminals, an effect that was also prevented by melatonin. These data show that melatonin is neuroprotective in this MPTP model of Parkinson's disease and suggest that melatonin, an endogenous antioxidant and nontoxic compound, may have potential beneficial effects for this neurodegenerative disorder.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1997

Effect of dopamine on immune cell proliferation in mice.

Dopamine is known as a precursor of catecholamine and one of the neurotransmitters in brain and peripheral tissues. Recent studies suggest an important role of dopamine in immune responses. In the present study, intraperitoneal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which lowered endogenous dopamine suppressed splenocyte proliferation in response to mitogens such as lipopolysaccharide (LPS) and concanavalin A (Con A). Moreover, intravenous injection of the specific agonists of dopamine DA-1 receptor (SKF38393) or DA-2 receptor (LY171555) into mice enhanced the splenocyte proliferation stimulated by LPS or Con A. In the in vitro cultures, dopamine, SKF38393 and LY171555 directly promoted cell proliferation to LPS or Con A. These results indicate that dopamine has an ability to regulate B- and T-cell proliferation both in vivo and in vitro.

Animals↗
PubMed2003

Protective role of group-II metabotropic glutamate receptors against nigro-striatal degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice.

To examine how mGlu2/3 metabotropic glutamate receptors affect nigro-striatal degeneration, we used the agonist, LY379268, and the antagonist, LY341495, in mice challenged with the nigro-striatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In control mice, high doses of MPTP (20 mg/kg, i.p., injected four times with 2 h of interval) induced a nearly total degeneration of the nigro-striatal pathway, as shown by measurements of striatal dopamine (DA) levels and by immunohistochemical analysis of tyrosine hydroxylase, high affinity dopamine transporter, and glial fibrillary acidic protein in the corpus striatum and substantia nigra. Lower cumulative doses of MPTP (30 mg/kg, i.p., injected only once) produced a partial lesion of the nigro-striatal pathway (about 50% reduction of striatal DA content). Systemic injection of LY379268 (1 mg/kg, i.p., 30 min prior to each injection of MPTP) partially reduced the extent of nigro-striatal degeneration induced by high doses of MPTP. Similar results were obtained by continuously delivering LY379268 (1 mg/kg/d for 7 d) by means of a subcutaneous osmotic minipump. The protective effect of LY379268 was antagonized by LY341495 (also delivered by the osmotic minipump). In mice challenged with the lower cumulative dose of MPTP, injection of LY379268 did not produce a significant neuroprotective effect. In contrast, the lesion was amplified by the antagonist, LY341495. Neither LY379268 nor LY341495 influenced the central bioavailability and the local half-life of MPTP, as shown by measurements of the toxin and its active metabolite, MPP(+), in the striatum. We conclude that mGlu2/3 receptors play a protective role against MPTP toxicity, and that the efficacy of the agonist, LY379268, critically depends on the extent of the nigro-striatal lesion.

Amino Acids↗
PubMed1998

Effect of melatonin on methamphetamine- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity and methamphetamine-induced behavioral sensitization.

Methamphetamine (METH)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity is thought to be associated with the formation of free radicals. Since evidence suggests that melatonin may act as a free radical scavenger and antioxidant, the present study was undertaken to investigate the effect of melatonin on METH- and MPTP-induced neurotoxicity. In addition, the effect of melatonin on METH-induced locomotor sensitization was investigated. The administration of METH (5 mg kg(-1) x 3) or MPTP (20 mg kg(-1) x 3) to Swiss Webster mice resulted in 45-57% depletion in the content of striatal dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, and 57-59% depletion in dopamine transporter binding sites. The administration of melatonin (10 mg kg(-1)) before each of the three injections of the neurotoxic agents (on day 1), and thereafter for two additional days, afforded a full protection against METH-induced depletion of dopamine and its metabolites and dopamine transporter binding sites. In addition, melatonin significantly diminished METH-induced hyperthermia. However, the treatment with melatonin had no significant effect on MPTP-induced depletion of the dopaminergic markers tested. In the set of behavioral experiments, we found that the administration of 1 mg kg(-1) METH to Swiss Webster mice for 5 days resulted in marked locomotor sensitization to a subsequent challenge injection of METH, as well as context-dependent sensitization (conditioning). The pretreatment with melatonin (10 mg kg(-1)) prevented neither the sensitized response to METH nor the development of conditioned locomotion. Results of the present study indicate that melatonin has a differential effect on the dopaminergic neurotoxicity produced by METH and MPTP. Since it is postulated that METH-induced hyperthermia is related to its neurotoxic effect, while regulation of body temperature is unrelated to MPTP-induced neurotoxicity or METH-induced locomotor sensitization, the protective effect of melatonin observed in the present study may be due primarily to diminishing METH-induced hyperthermia.

Animals↗
PubMed1990

Improvements in MPTP-induced object retrieval deficits and behavioral deficits after fetal nigral grafting in monkeys.

Improvements in MPTP-induced deficits were only found in subjects that received fetal substantia nigra transplants into the caudate nucleus. The MPTP-induced deficits were assessed using an object retrieval task that examined cognitive and subtle motor performance and by behavioral observation to determine the overall status of the subjects. Subjects that were also moderately or severely impaired by MPTP administration but that received inappropriate donor cells or implant sites (cerebellum to CN or SN to cortex) did not show any evidence of behavioral recovery. These subjects could not respond on the task in the months after grafting and were sacrificed, showing no improvements in parkinsonian signs or healthy behavior signs, up to 5-6 months after surgery. Grafting of SN cells into the striatum of non-MPTP lesioned subjects failed to modify normal behavior or induce abnormal behavior determined by our 2 behavioral assessment methods. In those monkeys that received the appropriate transplants, TH immunohistochemistry revealed that cells of the fetal substantia nigra grafted into the caudate nucleus survived and extended neurites into the host striatum. Indeed, grafted dopamine neurons were often associated with appreciable innervation of the caudate nucleus and appeared to be well incorporated into the host brain. In contrast, examination of the striatum of subjects in the inappropriate-graft group (e.g., cerebellar cells grafted into the caudate) showed no evidence of TH staining within the graft or host caudate nucleus. This indicated that there was no evidence of dopamine neurons present in the grafted tissue and that the mere presence of a fetal graft did not appear to induce sprouting in these MPTP-treated subjects. Although behavioral recovery occurred in only those monkeys that received appropriate transplants (fetal SN to host CN) and not in those that received inappropriate grafts (fetal cerebellum to CN or fetal SN to cortex), the CSF HVA levels did not distinguish those monkeys with improved parkinsonism from those that remained severely parkinsonian. The finding that in some SN-CN grafted subjects reported here, there was evidence of increased dopamine and lowered HVA/dopamine ratio in the vicinity of the SN grafts (cf. Elsworth et al., 1990b) is consistent with the hypothesis that graft-derived or graft-induced dopamine production is responsible for behavioral recovery. In addition, the finding that CSF HVA levels in non-MPTP lesioned subjects were unchanged by fetal SN grafts further indicates that CSF HVA levels may not be sufficiently sensitive to changes in central dopamine production to reflect release of dopamine from relatively small grafts that may, in lesioned subjects, modify behavior.(ABSTRACT TRUNCATED AT 400 WORDS)

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

Effects of ropinirole on motor behavior in MPTP-treated common marmosets.

The effects of ropinirole (4-[2-(dipropylamino)ethyl]-2-indolinone monohydrochloride), a nonergoline dopamine receptor agonist with a high affinity for native dopamine D(2)-like receptors, on Parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 2.5 mg/animal in common marmosets were examined and compared to the effects of bromocriptine. Ropinirole (0.1-3 mg/kg, PO) increased motor activity dose dependently and reversed akinesia or uncoordinated movement in MPTP-treated marmosets. The activities for ropinirole were very similar to those of bromocriptine. Ropinirole had, however, several properties that differed from those of bromocriptine. Ropinirole caused a more rapid onset of anti-Parkinsonian activity compared to bromocriptine, and had a potency more than five times greater than that of bromocriptine in the improvement of motor deficits. The combination of ropinirole and L-DOPA increased the effectiveness of ropinirole or L-DOPA alone, and produced a more marked additive effect on motor activity than did bromocriptine and L-DOPA. Chronic administration of ropinirole for 21 days produced a statistically significant increase in motor activity compared to the initial administration, and akinesia scores, measured through rating the quality of movements, were also improved without obvious dyskinesia. This study suggests that ropinirole is a dopamine D(2)-like receptor agonistic drug of potential use in the treatment of Parkinson's disease.

Animals↗
PubMed1997

Amphetamine induces hypermotility in MPTP-lesioned mice.

Two strains of mice (NMRI and C57B1/ 6) were treated with MPTP (within 8 h 4 x 30 mg/kg MPTP, IP) and motility was monitored 10 days later. An acute administration of amphetamine (2.5 mg/kg or 10.0 mg/kg) or apomorphine (0.5 mg/kg or 5.0 mg/kg) led to hypermotility and a dose-dependent increase of stereotyped behavior. Immunocytochemical investigations indicated a substantial loss of tyrosine-hydroxylase immunoreactivity in the basal ganglia which was accompanied by a 15% increase of 3H-spiroperidol binding to a striatal membrane preparation. No difference was found in biochemical and behavioral measures between both mice strains. Thus, MPTP-induced lesions in mice are probably followed by a denervation-like supersensitivity of the dopaminergic system, which might account for the finding that despite a severe degeneration of dopaminergic terminals amphetamine induces hypermotility.

Animals↗
PubMed1999

Effect of the dopaminergic neurotoxin MPTP on cocaine-induced locomotor sensitization.

The blockade of dopamine (DA) uptake via the dopamine transporter (DAT) in the nucleus accumbens (NAC) and striatum by cocaine has a major role in the reinforcing and psychomotor stimulating effects of the drug. Here we investigated the effect of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the expression and induction of sensitization to the locomotor stimulating effect of cocaine. MPTP (20 mg/kg x 4) caused 72 and 76% depletion of DAT sites in the NAC and striatum, respectively, in C57BL/6 mice. The magnitude of this depletion 3 and 19 days after MPTP administration was the same. To determine the effect of MPTP on the expression of the sensitized response to cocaine, cocaine-experienced mice (20 mg/kg for 5 days) received MPTP 3 days before a challenge cocaine injection was given on day 15. Cocaine/MPTP mice were significantly more sensitive to the challenge cocaine injection than the cocaine/saline-pretreated mice. To determine whether depletion of NAC and striatal DAT affects the induction of sensitization to cocaine, mice were pretreated with MPTP 3 days before the administration of cocaine (20 mg/kg for 5 days). The magnitude of the sensitized response of MPTP/cocaine-pretreated mice to cocaine challenge was the same as the sensitized response of mice treated with saline/cocaine, while the number of DAT binding sites in the MPTP/cocaine group was significantly lower than the saline/cocaine group. The present study indicates that MPTP exacerbates the expression of locomotor sensitization to cocaine, but it had no effect on the induction of sensitization. We conclude that the expression, but not the induction, of locomotor sensitization to cocaine may be dependent on the level of DAT binding sites.

Animals↗