I. Irwin

Selective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyrine (MPTP) in the squirrel monkey

1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) was administered via the intraperitoneal route to squirrel monkeys. Akinesia, rigidity and hypophonia were seen after repeated doses of 2 mg/kg. Postural tremor was present in one animal. Neuropathologic examination revealed cell loss restricted to the zona compacta of the substantia nigra. MPTP appears effective in producing an animal model for Parkinsons disease in the squirrel monkey, and may be one of the more selective neurotoxins described to date.

1-Methyl-4-phenylpyridinium ion (MPP+): Identification of a metabolite of MPTP, a toxin selective to the substantia nigra

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a newly described neurotoxin which selectively destroys cells in the substantia nigra when administered systemically to primates. Because the substance creates a condition in humans which is virtually indistinguishable from Parkinsons disease, interest has focused on its mechanism of action. We now report that MPTP appears to be rapidly metabolized after systemic administration in toxic amounts, and identify 1-methyl-4-phenylpyridinium ion (MPP+) as a probable major metabolite.

Toxic effects of MDMA on central serotonergic neurons in the primate: importance of route and frequency of drug administration.

This study compared the toxic effects of oral versus subcutaneous and single versus multiple doses of 3,4-methylenedioxymethamphetamine (MDMA) on central serotonergic neurons in non-human primates. Orally administered MDMA was approximately one-half as effective as subcutaneously administered drug. Multiple doses were more effective than single doses, but a single 5 mg/kg dose of MDMA given orally still produced a long-lasting depletion of serotonin in the monkey brain. These results indicate that when MDMA is given to monkeys in a manner similar to that employed by humans, it exerts toxic effects on central serotonergic neurons. This suggests that humans using MDMA may be at risk for incurring central serotonergic neuronal damage.

Aging and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced degeneration of dopaminergic neurons in the substantia nigra.

This study assessed the influence of aging on substantia nigra degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Extensive neuronal degeneration was found in the substantia nigra of older (8-12 months of age) but not younger (6-8 weeks of age) mice given MPTP. Older mice did not have higher brain concentrations of either MPTP or 1-methyl-4-phenylpyridinium (MPP+), the putative toxic metabolite of MPTP, to account for the greater toxicity. In fact, older mice metabolized MPTP more rapidly than younger mice, probably because of the increase in monoamine oxidase activity that occurs with aging. Striatal synaptosomes from older mice did not accumulate more [3H]MPP+ than synaptosomes from younger mice. Thus, it is concluded that the greater neurodegenerative effect of MPTP in older animals is not due to greater levels or uptake of MPP+, but rather is related to a true increase in sensitivity of older dopaminergic cells to MPTP. For comparative purposes, the toxic effect of another dopaminergic neurotoxin, methamphetamine, was tested. Older animals were not more sensitive than young mature animals to the toxic effect of methamphetamine. This finding indicates that the increased sensitivity of older dopaminergic neurons to MPTP is selective. The link established here between aging and the neurodegenerative effect of MPTP, a toxin which produces parkinsonism in humans, provides a mechanism by which an age-related neurodegenerative disorder such as Parkinsons disease could be caused by an MPTP-like toxin in the environment.

Dopamine uptake blockers protect against the dopamine depleting effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse striatum

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a recently described neurotoxin, produces a marked dopamine (DA) depletion in the mouse striatum. In this study, a series of DA uptake blockers was tested for their ability to prevent this effect of MPTP. The agents tested (amfonelic acid, benztropine, bupropion and mazindol) completely protected against DA depletion in the mouse striatum when given before DA-depleting doses of MPTP were administered, whereas atropine and trihexyphenidyl (which were employed for comparative purposes) did not. DA uptake blocking agents appear to represent a second general class of compounds, monoamine oxidase inhibitors being the first, which protect against the biologic effects of MPTP in the mouse.

5-Hydroxyindoleacetic acid in cerebrospinal fluid reflects serotonergic damage induced by 3,4-methylenedioxymethamphetamine in CNS of non-human primates.

This study examined whether 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) could be used to detect serotonergic damage induced by (+/-)-3,4-methylenedioxymethamphetamine (MDMA) in the central nervous system (CNS) of non-human primates. Monkeys were administered toxic doses of MDMA; two weeks later, the animals were lightly anesthetized with ether and CSF was obtained by means of cervical puncture. Later that same day, the animals were killed for direct determination of CNS serotonin and 5-HIAA concentrations. Monkeys with 73-94% depletions of serotonin and 5-HIAA in brain and 42-45% depletions of serotonin and 5-HIAA in the spinal cord had a 60 +/- 7% reduction of 5-HIAA in CSF, without any change in homovanillic acid (HVA) or 3-methoxy-4-hydroxyphenethyleneglycol (MHPG). These findings indicate that CSF 5-HIAA can be employed to detect central serotonergic damage produced by MDMA in non-human primates, and suggest that CSF 5-HIAA may be useful for detecting MDMA-induced neuronal damage in humans.

Orally administered MDMA causes a long-term depletion of serotonin in rat brain

Recent studies suggest that 3,4-methylenedioxymethylamphetamine (MDMA), when administered subcutaneously, is toxic to central serotonergic neurons in rats. Because humans typically self-administer this drug orally, we compared this route to the s.c. route of administration. Orally administered MDMA produced a dose-related depletion of serotonin comparable to that produced by the s.c. route. These findings suggest that MDMA, when given orally, retains it neurotoxic activity and that humans using MDMA may be at risk for developing a persistent depletion of brain serotonin.

VII. The biotransformation of MPTP and disposition of MPP+: Tge effects of aging

Abstract The primary objective of this study was to investigate possible biochemical correlates of the enhanced effects of MPTP with aging in C57BL/6 mice. Striatal MPP + concentrations were found to increase directly with the age of the animals injected (range 6 to 32 weeks). In vitro studies confirmed an enhanced rate of production of MPP + in striatum, ventral mesencephalon, and frontal cortex in older animals. The rate of clearance of MPP + from striatum was approximately the same in 6–8 week old mice as in 8 month old mice, but the total exposure of this brain region to MPP + was approximately three times greater when older animals were compared to younger ones given equivalent doses of MPTP. These results are compatible with increased MPP + production (i.e., a pharmacokinetic effect) as the explanation for the increased dopamine depletion induced by MPTP in older animals. We suggest that this approach may provide a new avenue of investigation for the study of neurodegenerative phenomena and the aging process.

3,4-Methylenedioxyethylamphetamine (MDE), a novel analogue of MDMA, produces long-lasting depletion of serotonin in the rat brain

The present study was carried out to asses possible toxic effects of 3,4-methylenedioxyethylamphetamine (MDE) on serotonergic, dopaminergic or noradrenergic neurons in the rat brain. It was found that MDE produced a long-lasting, dose-related depletion of serotonin (5HT). However, even at high dosage, MDE did not reduce the concentration of either dopamine (DA) or norepinephrine (NE) on a long-term basis. When compared to 3,4-methylenedioxymethylamphetamine (MDMA), MDE was approximately one fourth as potent as producing a long-term depletion of 5HT. These results suggest that MDE, like MDMA, may be selectively toxic to central serotonergic neurons.

The importance of the ‘4–5’ double bond for neurotoxicity in primates of the pyridine derivative MPTP

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a newly recognized neurotoxin which selectively damages the cells of the substantia nigra in primates. It has been effective in producing an animal model for Parkinsons disease. We now report that saturating the 4-5 double bond in the tetrahydropyridine ring of MPTP prevents its metabolic oxidation to 1-methyl-4-phenylpyridinium ion (MPP+) and removes its behavioral and neurotoxic effects. We believe that this represents an important step towards elucidating the mechanism of action of this compound.