MPTP—

Dopaminergic neurotoxin that causes parkinsonism via lesion of nigrostriatal dopamine neurons in rat, mice, monkeys. Unlike the dopaminergic neurotoxin MPTP (N-methy 1-4-phenyl-1,2,3,6-tetrahydropyridine) it does not cross the blood-brain barrier. 

A synthetic neurotoxin that causes parkinsonism in human and nonhuman primates, mice, gold fish, and dogs. MPTP is inert but metabolized by MAO-B to the neurotoxin MPP+ (1,2-dihydropyridine ion). This neurotoxin causes depletion of dopamine and degeneration of nigrostriatal dopamine neurons similar to what is observed in Parkinson s disease. 

Toxins that gain access to a neuron through its uptake process and then destroy it in some way. This approach has been used mainly to destroy monoamine neurons with 5,6 or 5,7-dihydroxytryptamine targeting 5-HT neurons, 6-hydroxydopamine for dopamine (and to a lesser extent noradrenergic) neurons and MPTP for dopamine neurons (see Chapter 7). Only the latter is fully specific and effective systemically. The others need to be administered directly into the appropriate brain areas and while they may only affect the intended NT neurons, the injection may not affect all of them. 

The removal of released DA from the synaptic extracellular space to facilitate its intraneuronal metabolism is achieved by a membrane transporter that controls the synaptic concentration. This transporter has been shown to be a 619 amino-acid protein with 12 hydrophobic membrane spanning domains (see Giros and Caron 1993). Although it has similar amino-acid sequences to that of the NA (and GABA) transporter, there are sufficient differences for it to show some specificity. Thus DA terminals will not concentrate NA and the DA transporter is blocked by a drug such as nomifensine which has less effect on NA uptake. Despite this selectivity some compounds, e.g. amphetamine and 6-OHDA (but not MPTP), can be taken up by both neurons. The role of blocking DA uptake in the central actions of cocaine and amphetamine is considered later (Chapter 23). 

Recently much interest has centred on a very specific toxin for DA neurons. This is 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP). It was discovered when a student, who was addicted to pethidine, tried to manufacture l-methyl-4-phenyl-4-propionoxy-piperidine (MPPP) but took a short-cut in synthesis and produced MPTP. When he administered this to himself he developed Parkinsonism. MPTP destroys DA neurons. Again this process depends on the neuronal uptake mechanism, since MPTP itself is not the active material. It needs to be deaminated to MPP+ which is then taken up by DA nerve terminals. 

Since PD is caused by a relatively specific degeneration of the DA nigrostriatal tract and as there are specific toxins, for DA neurons, i.e. 6-OHDA and MPTP, it should be possible to produce appropriate experimental models. Certainly both toxins cause rotational behaviour in rats (Fig. 7.7) but no rodent shows a syndrome suggestive of PD. Tremor and akinesia can be seen, however, in primates after such toxins and these are being more widely used in experimental studies of PD and drug evaluation. Reserpine causes a depletion of all brain monoamines and produces motor defects in rats, which, even if not PD-like, do respond to DA manipulation. 

Preliminary data indicate that in the reserpinised rat or MPTP marmoset, the enkephalin agonist (SNC80) reduces PD-like symptoms without causing increased activity, i.e. no trend to dyskinesias. Enadoline, a dynorphin-like kappa opioid agonist also has similar effects in the same models. Whether it would be similar in humans remains to be seen. 

Nitric oxide has also been implicated in PD. Thus animals with MPTP-induced Parkinsonism not only show extensive gliosis in the substantia nigra (like humans) in which the glial cells produce NO, but Liberatore and colleagues have found that in iNOS (inducible nitric oxide synthase) knock-out mice the toxicity of MPTP is halved. Since NO releases iron from ferritin and produces toxic peroxinitrate in the presence of superoxide radicals it could accelerate, even if it does not initiate, dopaminergic cell death (see Hirsch and Hunot 2000 for further details). 

Jolkkonen, J, Jenner, P and Marsden, CD (1995) L-Dopa reverses altered gene expression of substance P but not enkephalin in the caudate-putamen of common marmosets treated with MPTP. Brain Res. Mol. Brain Res. 32 297-307. 

Treseder, SA, Jackson, M and Jenner, P (2000) The effects of central aromatic amino acid (dopa) decarbosylase inhibition on the motor actions of L-dopa and dopamine agonists in MPTP-treated primates. Brit. J. Pharmacol. 129 1355-1366. 

My answer always is that no one has yet done a detailed neurobehavioral study of these individuals and the deficit that they may have. It may be very subtle in nature, and 1 am not sure that we have the methods available to detect and quantify those deficits. The fact that these people are not walking in with overt behavioral disturbances as the people with MPTP did. 1 think, is related to the fact that, one, they may not have the kind of neurotoxicity we are suspecting, and two, if they do, the kind of functional consequences that you may get from serotonergic dysfunction may be much more subtle than the kind of functional consequences you get with dopamine dysfunction, where it is very easy to recognize the parkinsonian patient... 

Langston, J.W. Fomo, L.S. Rebert, C.S. and Irwin, I. Selective nigral toxicity after systemie administration of 1-methyl-4-phenyl-1,2,5,6-tetra-hydropyridine (MPTP) in the squirrel monkey. Brain Res 2 390-394, 1984. 

The neurotoxic effects of all these compounds are antagonized by inhibitors of monoamine uptake (table 1), implicating the membrane uptake carrier on serotonin and dopamine neurons in the mechanism of neurotoxicity. In this regard, these amphetamines are like a drug somewhat related in structure, namely l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), a Parkinsonism-causing neurotoxic dmg that has been studied intensely since 1983 (Langston and Irwin 1986). In the case of MPTP, the mechanism by which inhibitors of the dopamine uptake carrier block the neurotoxicity toward dopamine neurons (mainly nigrostriatal dopamine neurons) seems clear. A metabolite of MPTP, l-methyl-4-phenylpyridinium (MPP-I-), has been shown to be a substrate for the dopamine uptake carrier (Javitch et al. 1985). Thus accumulation of MPP-I-, formed metabolically from... 

MPTP, into dopamine neurons seems to be essential, and blockade of that aeeumulation prevents the neurotoxieity. MPP+ also ean be transported into norepinephrine neurons (Javitch et al. 1985), leading to neurotoxicity toward cortical norepinephrine neurons, an effect blocked by inhibitors of the norepinephrine uptake carrier (Sundstrom and Jonsson 1985). 

Rats that have lost dopamine and/or serotonin terminals following treatment with amphetamine, methamphetamine, MDMA, MDA, / -chloroamphetamine, or fenfluramine show little in the way of overt ehanges in appearanee or behavior. Dr. Rieaurte (this volume) emphasized the need for more studies in primates, since MPTP-treated miee also show little in the way of observable functional changes, whereas MPTP-treated monkeys show marked neurologie deficits. It may be neeessary to do more detailed analysis of speeifie behaviors and other funetional outputs that are influeneed by dopamine and/or serotonin neurons, to detect functional deficits induced by some neurotoxic drugs. For instance, specific behaviors sueh as appetite-eontrolled behavior (Leibowitz and Shor-Posner 1986), murieidal behavior (Katz 1980), and sexual behavior (Tucker and File 1983) elieited by drugs... 

COMMENT I would like to know why you thought the amphetamine model of dopamine neurotoxicity might be more suitable or more revealing for the study of Parkinson s disease than the MPTP model. 

RESPONSE We do not understand all there is to know about the mechanisms of MPTP neurotoxicity, but it seems to involve MPP+, which is potentially cytotoxic to all cells but that attains toxic concentrations after MPTP administration only in cells that concentrate MPP+. Dopamine apparently is not involved in the neurotoxic effects of MPTP. I am attracted to the idea that dopamine itself may be involved in the etiology of Parkinson s disease, that dopamine neurons may be at risk because of the nature of their neurotransmitter. 

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