Abstract

Section 1

Section 2

Section 3

Section 4

Section 5

Discussion
Board

A. NORMAL FUNCTIONS

(i) Catecholamine ortho-quinones (CAQs) are necessary precursors in the biosynthesis of neuromelanin (NM) (Bindoli et al. 1992; Costa et al, 1992). Therefore the presence of NM in a neuron necessitates the presence of the relevant CAQ as well. NM occurs in abundance in the dopaminergic cells of the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA), in the noradrenergic cells of the locus coeruleus (LC) and is also found in the A1-A3 noradrenergic nuclei in the medulla (Bogerts, 1981; Saper & Petito, 1982). In the case of the C1- C3 adrenergic nuclei in the medulla Gai et al (1993) have presented evidence that very few of the adrenergic neurons are pigmented. However, adrenochrome may be formed but not metabolized as far as neuromelanin. Its chief metabolite is adrenolutin which does not form neuromelanin readily (Solano, 1998).

Neuromelanin is not found in these cells at birth but appears at around 6 months of age and then steadily accumulates during life. Therefore dopaminochrome, and noradrenochrome must (and adrenochrome may) occur in the brain together with related compounds on the NM biosynthetic pathway and must be continually produced during life.

(ii) The presence of 5-cysteinyl dopamine in brain (Carlsson et al. 1994) also indicates that DAQs are present too since it is a metabolite of dopamine o-quinone.

(iii) The enzymes DT-diaphorase and NADPH P450 cytochrome reductase that interconvert DAQs are present in brain (Segura-Aguilar, 1996).

(iv) There is now considerable evidence that dopamine neurotoxicity is mediated by DAQs acting not on DA receptors but on NMDA glutamate receptors (Michel and Hefti, 1990; Cadet and Kahler, 1994; Ben-Sacher et al. 1995). This suggests that DAQs are located so that they can reach NMDA receptors.

(v) NM is confined to cell bodies and large proximal dendrites.

(vi) The o-semiquinone free radical form of CAQs are potent neurotoxins, bind covalently to SH groups on proteins and inactivate enzymes such as COMT.

(vii) Very little is known about the basic pharmacology of CAQs derived from dopamine and norepinephrine. More is known about adrenochrome (the CAQ derived from adrenaline). It inhibits COMT (Urabe et al. 1994), promotes the synthesis of prostaglandins in brain tissue in vitro (White and Wu, 1975) promotes the secretion of nerve growth factor by L-M cells (Napolitano et al. 1993), inhibits hexokinase and succinic dehydrogenase (Grof, 1963), and acts as a powerful stimulant of guanylcyclase activity in cell free systems (Liang and Sacktor,1978). But it is not clear which, if any, of these have physiological significance. There is one report that 5,6-dihydroxyindole is cytotoxic (Urabe et al. 1994). It also inhibits certain lipoxygenases (Napolitano et al., 1993). More work done in this area may be expected to produce some data to work on.

(viii) Adrenochrome (or some metabolite such as adrenolutin—the 5,6-dihydroxyindole derivative of adrenaline) has been shown to be psychotomimetic in humans (Hoffer et al. 1954; Schwartz et al. 1956a; Taubman and Jantz, 1957; Grof, 1963) and to produce abnormal EEG patterns in humans and abnormal EEG changes and behaviors in animals similar to those produced by LSD (Schwartz et al, 1956b; Taborsky, 1968).

(ix) Outside the brain adrenochrome has been reported to be the principle metabolite of adrenaline by polymorphonuclear leucocytes (Matthews et al, 1985). Dhalla et al (1989) have reported that adrenolutin, but not adrenochrome, occurs in normal plasma. This claim certainly needs confirmation.

(x) Catecholamines in the brain are protected against auto-oxidation by cellular antioxidants, in particular ascorbate, glutathione (GSH) and possibly other antioxidants such as carnosine, uric acid, metatonin and others.

(2) What we don’t know.

(i) Where are CAQs formed?

Since NM is found only in the cell body, presumably the final stage of its synthesis—the polymerization of 5,6-dihydroxyindole—must occur in the cytoplasm of the neurone. There is no evidence that NM is transported anywhere. However, any of its soluble precursors may be formed elsewhere and transported to the cell body. Furthermore CAQs formed elsewhere—in the synapse for example—may be metabolized to non-toxic 0-methylated derivatives of the o-hydroquinone or of 5,6-dihydroxyindole, which are then excreted in the urine. Thus CAQs formed do not have to end up as neuromelanin. As we will see one important possible site of DAQ formation is inside the glutamate synapse. Catecholamines inside their synaptic vesicles are well protected against oxidation by high ascorbate and carnosine levels. But the cytoplasm and the synaptic cleft offer more oxidative environments. Dopamine is released from dendrites in the SN and VTA (Nirenberg 1997) and so could oxidize locally to form NM.

Enzymes capable of oxidizing catecholamines to o-quinones in vitro include xanthine oxidase (whose levels in brain are low), dopamine beta-monoxygenase, monoamine oxidase and prostaglandin H synthase (cyclo-oxygenase). The last is an important enzyme in the post-synaptic cascade of the NMDA receptor. So where is dopamine likely to come into contact with PGH synthase? One locus might be the post-synaptic cascade of the NMDA receptor in the synapses formed by glutamatergic axons, arising from the prefrontal cortex, on the dopaminergic axons in the striatum (Burns et al. 1994; Grace et al. 1998). Another locus could be glutamatergic synapses on dopaminergic neuronal bodies.

But where could dopamine come into contact with PGH synthase inside the glutamatergic neuron? A large proportion of dopamine receptors, when activated by dopamine, are internalized into the post-synaptic neuron by endocytosis (Dumartin et al. 1998) together with the bound neurotransmitter (Koenig and Edwardson 1997). This endocytosis was described by Dumartin et al. (1998) as “acute” (within ~4 minutes) and “dramatic”. So this might enable dopamine and PGHsynthase to interact. But it is uncertain if the small amount of dopamine that could be internalized by this mechanism could be effective. However, these redox cycling mechanisms act rather like enzymes and allow a small quantity of the recycling agent chemically to alter a large quantity of what is being recycled (Segura-Aguilar 1998). Polypeptide neuromodulators internalized by endocytosis are known to take part in the subsequent post-synaptic metabolic pathways (Koenig & Edwardson, 1997). However, which of these enzymes, if any, actually oxidizes catecholamines in vivo remains to be determined.

(ii) What is the normal function(s), if any, of CAQs?

In the past NM has been regarded as a mere ‘waste-product’ of catecholamine metabolism (Bogerts, 1981). However, its precursors may exert some normal function in the brain—if so, what? One role may have to do with synaptic plasticity. One has to ask oneself what normal function could potent neurotoxins like catecholamine o-semiquinones have if not deletion of unwanted tissue such as spines that are no longer required. Glutamate synapses are carried mainly on dendritic spines. Spines are highly dynamic structures and are continually being pruned and formed (Quartz and Sejnowski 1997). In the NMDA receptor post-synaptic cascade the activation of PGHs and NOs both lead to the release of AA as well as large amounts of ROS including H2O2. NO, AA and H2O2 are all freely diffusible molecules and can diffuse back into the synaptic cleft. NO exists mainly as the strongly oxidant neurotoxic nitric oxide radical NO.. Furthermore NO reacts with the superoxide anion to form the potent oxidant peroxynitrite. Any of these oxidant molecules could contribute to spine pruning.

Another key factor in this redox equation may be catecholamines, particularly dopamine. Many glutamate synapses have a dopaminergic bouton-en-passage closely attached to one side allowing diffusion of dopamine released into the glutamate synapse. Moreover it has recently been discovered (Sulzer et al, 1998) that many dopaminergic neurones have dopaminergic boutons-en-passage close to the target neuron but, contrary to Dale’s principle, have glutamatergic terminals that synapse with proximal dendrites of the target neuron via asymmetric synapses. Thus stimulation of these VTA neurons results in a fast glutamate mediated response in the target neuron and a slow dopamine-mediated response which acts partly presynaptically via DA receptors to inhibit glutamate release and may act partly by a redox mechanism on the glutamatergic synapse by the mechanism suggested in this paper. Catecholamines are potent antioxidants (Liu & Mori, 1993). Dopamine is released widely in the brain, in particular in the frontal cortex, following the receipt of positive reinforcement by the organism. Therefore, such release could tilt the redox balance inside the glutamate synapse towards the neuroprotective antioxidant side allowing synaptic growth promoted, for example, by metabotropic glutamate receptors. This would tend to promote those circuits active at the time of glutamate release. Whereas circuits active during periods of low dopamine release would lack this antioxidant growth-promoting effect and could even be deleted by an excess of oxidant molecules. This biochemical system may play a role in synaptic plasticity, neurocomputation and learning (see Smythies, 1997 for details). This mechanism is proposed as an addition not a replacement in addition to the many specific pre-and post-synaptic dopamine receptor-mediated mechanisms at the glutamate synapse.

However, in the case of most physiological antioxidants like vitamin E and ascorbate, the oxidized form that results from interaction with the free radical is not itself a highly toxic molecule, and, moreover, it is converted back into the active form by additional mechanisms involving a chain of antioxidants—e.g. glutathione, alpha-lipoic acid, caretenoids, and NADH, as well as vitamin E and ascorbate for each other (Chan 1993; Böhm et al. 1997). Dopamine at first sight might appear to be an unsatisfactory candidate for an antioxidant role, since dopamine oxidation leads eventually to the production of highly toxic free radical o-semiquinones, which cannot be reconverted into dopamine, as well as large amounts of new ROS. However, the first stage of dopamine oxidation is the conversion of dopamine to the uncyclized dopamine quinone. This stage is fully reversible by ambient antioxidants such as ascorbate and glutathione thus setting up a typical redox cycle. Dopamine quinone may then be further metabolized by three routes:—
(i) to form 5-cysteinyldopamine, which is also an antioxidant and chelator of ferric ions (Napolitano et al, 1993),
(ii)to form 5-glutathionyldopamine, which is also an antioxidant (Baez et al, 1997; Cuénod et al, 1997),
(iii) irreversible ring closure to form dopaminochrome.

Dopaminochrome may then be metabolized either of two routes. The first is by the enzyme DT-diaphorase to form the relatively non-toxic dopamine o-hydroquinone, which is then converted into O-methylated or sulfated products which are excreted. The second route is by the enzyme NADPH cytochrome P450 reductase to form the highly toxic free radical dopamine o-semiquinone. Both the hydroquinone and the semiquinone are then converted to 5,6-dihydroxyindole, which polymerizes to form neuromelanin. Thus, in an environment with sufficient ambient antioxidants dopamine could act as an antioxidant by reducing an ROS and being converted into dopamine o-quinone in the process. The ambient antioxidants then convert the dopamine o-quinone back to dopamine, thus providing the necessary redox recycling mechanism. Support for this hypothesis is provided by the observation that dopamine oxidizes to its o-quinone more rapidly, and the o-quinone cyclizes more slowly to its aminochrome, than do other catecholamines (Hawley et al. 1967; Graham, 1979). The production of the toxic o-semiquinone and additional ROS production is thus avoided. 5-cysteinylization and 5-glutathionylization may form the major routes of metabolism of dopamine quinone and ring closure, leading to the production of toxic o-semiquinones and further ROS terminating in neuromelanin formation, may occur only when supplies of cysteine and glutathione are exhausted (Carstam et al. 1991; Odh et al. 1994; Cheng et al. 1996). This redox cycling mechanism between dopamine and dopamine quinone would provide for modulation of the redox state of the glutamate synapse resulting in spine growth or deletion in synchrony with the reinforcement status of incoming stimuli as signaled by volume dopamine release. The other synaptic antioxidants acting by themselves could not respond in this manner.

It might also be argued that the dopamine content of the cortex is too low to support the purely chemical reactions suggested by this hypothesis. However the overall level is not what is important. What is important is the level at each glutamate synapse. Since many of these have a dopamine bouton-en-passage immediately adjacent (Kötter 1994), I would argue that this might provide the quantity of dopamine required. However, in a low antioxidant environment, dopamine can auto-oxidize, either spontaneously or under the influence of peroxinitrite, or other oxidant including free iron, to form neurotoxic o-quinones. If the level of dopamine released is insufficient to maintain a reductive redox potential in the glutamate synapse, yet sufficient to yield a toxic level of DAQs upon oxidation, then this mechanism may contribute to spine pruning.

This system can be further investigated by several routes:

(i) Urinary, CSF and brain tissue levels of stable intermediates in neuromelanin formation from the three catecholamines, such as the 5,6-dihydroxy indoles and their O-methylated products, can be examined in various situations.

(ii) The present work on 5-cysteinyl dopamine needs to be extended and complemented by work on the 5-cysteinyl derivatives of noradrenaline and adrenaline and on 5-glutathionyl derivatives of all three catecholamines and in additional brain areas besides the striatum. Furthermore 5-cysteinyl adrenaline should be looked for in the C1-C3 medullary group.

(iii) The status of neuromelanin in schizophrenia has been the subject of some preliminary investigations which showed abnormalities in some cases. This needs to be repeated with more subjects and extended to include the C1-C3 group of neuromelanin-containing neurons.

(iv) The claim made by Gai et al (1993) that the neuromelanin-containing cells in the medulla do not contain PNMT, and are thus not adrenergic, needs to be confirmed. It should be noted that the material they used came from severe cases of Parkinson’s disease who had lost up to 50% of their C1 and C3 pigmented neurons. This work needs to be repeated using material from normal subjects.

(v) The question as to the mode of psychotomimetic action of adrenochrome needs to be addressed. Clinically its effects appear to be more like those of cannabis than LSD and it has been classified as an ‘imagery-producing psychodysleptic’ (Smythies, 1999). Similar studies need to be carried out on the o-quinone derivatives of dopamine and norepinephrine. Since human work is hardly possible these days, animal models need to be employed. Adrenochrome is easier to work with as it is a more stable molecule. Pharmacological studies on its effects on serotonin, cannabinoid, NMDA and other relevant receptors might produce some interesting

B. WHAT IS THE ROLE OF CA-0-QUINONES IN DISEASE?

Since the disease is due to the destruction of the neuromelanin-containing neurons of the SNpc and locus coeruleus (as well as the C1-C3 medullary group) CAQs may well be involved (Hirsch 1994). Neuromelanin is normally neuroprotective as it chelates toxic heavy metals and has antioxidant properties (Korytowski et al. 1995). But in excess it becomes neurotoxic (Enochs et al. 1994). Many workers have linked PD to excess heavy metals in the environment. (e.g. Enochs et al. 1994; Goldsmith et al. 1990). The substantia nigra in PD is the site of increased oxidative stress, increased pro-oxidant iron levels and reduced antioxidant defenses (Castellani et al, 1996; Drukarch et al, 1997; Toffa et al. 1997; Pearce 1997; Zhang and Dryhurst, 1994)). MAO activity is increased (Drukhardt et al. 1997) as are levels of pro-oxidant NO radicals (Nishibayashi et al. 1996) in the SNpc in PD.

The excess iron accumulates within the degenerating NM-containing neurons (Lereugle et al. 1996). Much of this is bound in the ferric form to the iron-binding protein lactotransferrin (Lereugle et al. 1996). Serum transferrin receptor concentration strongly correlates with mortality from in PD cases but not in controls (Marder et al. 1998). The Lewy bodies have increased activity of haem oxygenase which produces free iron (Schipper et al. 1998). In this connection it is of interest that Muthane et al. (1998) have reported from a study in India that Hindu’s have 40% lower levels of melanized neurons in the SNpc that do Europeans as well as a very low incidence of PD, whereas they report that Parsees in India have an incidence of PD equivalent to the high level in industrialized countries. Poor rural Muslims also have a low incidence of PD (Razdan et al, 1994). Hindus and poor rural Muslims have an almost exclusively vegetarian diet, whereas the wealthier Parsees eat meat. But perhaps more importantly Indians eat large amounts of curry spices that strongly inhibit iron adsorption (Fleming et al. 1998). Curiously vitamin C is a potent enhancer of iron adsorption (Fleming et al. 1998; Cook, 1998). This suggests that PD cases should eat plenty of curry but avoid vitamin C supplements. Mice given iron overload developed low levels of GSH, high GSSG and high levels of hydroxyl radicals but not increased levels of lipid peroxidation (Lan & Jiang. 1997). However, these mice were much more susceptible than normal to the neurotoxin MPTP. These authors concluded that high dietary levels of iron induce oxidative stress but not neuronal damage, which needs a second triggering factor. One such factor may be low activity of COMT (Kunugi, 1997): COMT protects against the formation of toxic catecholamine o-semiquinones by O-methylation of the hydroquinone.

The question of whether free iron occurs in the brain under normal circumstances is controversial (Koppenol 1998; Mumby et al. 1998) although it may be relevant to disease states. Free iron is a potent converter of catecholamines to CAQs. Furthermore, CAQs release free iron from ferritin (Tanaka, 1997). There is also evidence in PD of an increase in the oxidative pathway of DA metabolism— DAQ synthesis is raised in the SN (Mattammal et al. 1995) and the 5-cysteinyldopamine/HVA ratio is raised in CSF (Cheng et al. 1996) and the 5-cysteinyldopamine/DOPAC ratio is raised in the severely degenerated SNpc in PD (Fornstedt et al. 1989). Furthermore, although GSH levels in the SNpc are low there is no concomitant increase in GSSG levels (Shen et al. 1996). This suggested that the low GSH level is not due to its consumption as an antioxidant but to a high level of complex formation with excess levels of DA and NE o-quinones. Lewy bodies consist of neurofilaments thought to be cross-linked by DA o-quinones (Montine et al. 1995). In conclusion there is good evidence that CAQs (together with increased iron levels, increased oxidative stress and reduced antioxidant defenses) may be closely involved in the pathobiochemistry of PD but much more work is needed to determine the exact mechanism involved.

(2) Schizophrenia.

I have recently covered this topic extensively elsewhere (Smythies, 1997). Briefly the evidence that CAQs may be involved in schizophrenia is:—

(i) Adrenochrome is a psychotomimetic agent with effects more similar to those produced by cannabis than LSD (Hoffer et al, 1954; Schwartz et al. 1996a,b; Jantz and Taubman, 1998; Grof, 1963). No such tests have been carried out with dopaminochrome or noradrenochrome. Adrenochrome may occur in the C1-C3 adrenergic neurons in the medulla that project to key midline limbic thalamic nuclei. However more work is necessary to determine this.

(ii) Schizophrenics have increased brain levels of 5-cysteinyl dopamine.

(iii) Schizophrenics are weak in the enzymatic mechanisms that protect against CA o-semiquinone formation i.e. transmethylation reactions (weak MAT and SHMT) and antioxidant defenses.

(iv) There are preliminary reports that neuromelanin itself is abnormal in some cases of schizophrenia.

References

1. Baez S, Segura-Aguilar J, Widersten M, Johansson AS, Mannervik B.(1997) Glutathione transferase catalyzes the detoxification of oxidized metabolites (o-quinones) of catecholamines and may serve as an antioxidant system preventing degenerative cellular processes. Biochemical Journal, 324:25-28.
2. Ben-Shachar D, Zuk R and Glinka Y. (1995) Dopamine neurotoxicity: inhibition of mitochondrial respiration. Journal of Neurochemistry, 64: 718-723.
3. Bindoli A, Rigobello MP, Deeble DJ. (1992) Biochemical and toxicological properties of the oxidation products of catecholamines. Free Radical Biology and Medicine, 13:391-405.
4. Bogerts, B. (1981) A brainstem atlas of catecholaminergic neurons in man, using melanin as a natural marker. Journal of Comparative Neurology, 197:63-80.
5. Böhm F, Edge R, Land EJ, McGarvey DJ, Truscott TG.(1997) Caretenoids enhance vitamin E antioxidant efficiency. Journal of the American Chemical Society, 119:621-627.
6. Burns LH, Everitt BJ, Kelley AE, Robbins TW. (1994) Glutamate-dopamine interactions in the ventral striatum: role of locomotor activity and response with conditioned reinforcement. Psychopharmacology, 115:516-528.
7. Cadet JL, Kahler LA. (1994) Free radical mechanisms in schizophrenia and tardive dyskinesia. Neuroscience and Biobehavioural Reviews, 18: 457-467.
9. Carlsson A, Waters N, Hansson LO. Neurotransmitter aberrations in schizophrenia: new findings. In: R. Fog, J. Gerlach and R. Hemmingsen (Eds), Schizophrenia. An Integrated View. Copenhagen, Munksgard,1994.
10. Carstam R, Brinck C, Hindemith-Augustsson A, Rorsman H, Rosengren E. (1991) The neuromelanin of the human substantia nigra. Biochimica et Biophysica Acta, 1097:152-160.
11. Castellani R, Smith MA, Richey PL, Perry G. (1996) Glycoxidation and oxidative stress in Parkinson’s disease and diffuse Lewy body disease. Brain Research, 737:195-200.
12. Chan, AC. 1993 Partners in defense, vitamin E and vitamin C. Canadian Journal of Physiology and Pharmacology, 71:725-731
13. Cheng F-C, Ko J-S, Chia L-G, Dryhurst G. (1996) Elevated 5-S-cysteinyldopamine/homovanillic acid ratio and reduced homovanillic acid in cerebrospinal fluid: possible markers for and potential insights into the pathobiology of Parkinson’s disease. Journal of Neural Transmission, 103:433-446.
14. Cook JD. (1998) Food iron availability: back to the basics. American Journal of Clinical Nutrition, 67:593-594.
15. Costa, C., Bertazzo, A., Allegri, G., Toffano, G., Curcuruto, G., and Traldi, P. (1992) Melanin biosynthesis from dopamine: II A mass spectrometric and collisional spectroscopic investigation. Pigment Cell Research, 5:122-131.
16. Cuénod M, Do KQ, Lauer CJ, Hulsboer F. (1997) Could a glutathione model integrate both dopamine and glutamate hypothesis of schizophrenia? Biological Psychiatry, 42:287S
17. Dhalla KS, Ganguly PK, Ropp H, Beamish RE, Dhalla NS. (1989) Measurement of adrenolutin as an oxidative product of catecholamines in plasma. Molecular and Cellular Biochemistry, 87:85-92.
18. Drukarch B, Langeveld CH, Stoof JC. (1997) Glutathione homeostasis is linked to the vesicular storage of dopamine in rat PC12 pheochromocytoma cells. Experimental Neurology, 145:S39.
19. Dumartin B, Caillé I, Gonon F, Bloch B. (1998) Internalization of D1 dopamine receptor in striatal neurons in vivo as evidence of activation by dopamine agonists. Journal of Neuroscience, 18:1650-1661.
20. Enochs, W.S., Sarna, T. Zecca, L. Riley, P.A. and Swartz, H.M. (1994) The roles of neuromelanin, binding of metal ions and oxidative cytotoxicity in the pathogenesis of Parkinson’s disease: an hypothesis. Journal of Neural Transmission [P-D Section], 7:83-100.
21. Fleming DJ, Jacques PF, Dallal GE, Tucker KL, Wilson PWF, Wood RJ. (1998) Dietary determination of iron stores in free-living elderly population: the Framingham Heart Study. American Journal of Clinical Nutrition, 67:722-730.
22. Fornstedt B, Brun A, Rosengren E, Carlsson A. (1989) The apparent autoxidation rate of catechols in dopamine-rich regions of human brains increases with the degree of depigmentation of substantia nigra. Journal of Neural Transmission, 1:279-295.
23. Gai W-P, Geffen LB, Denoroy L (1993) Loss of C1 and C3 epinephrine-synthesizing neurons in the medulla oblongata in Parkinson’s disease. Annals of Neurology, 33:357-367.
24. Goldsmith JR, Herishanu Y, Abarbanel JM, Weinbaum Z. (1990) Clustering of Parkinson’s disease points to environmental factors. Archives of Environmental Health, 45:88-94.
25. Grace AA, Moore H, O’Donnell P. (1998) The modulation of corticoaccumbens transmission by limbic afferents and dopamine: a model for the pathophysiology of schizophrenia. Advances in Pharmacology, 42:721-724,
26. Graham, D.G. (1979) On the origin and significance of neuromelanin. Archives of Pathology and Laboratory Medicine, 103:359-362.
27. Grof, S. (1963) Clinical and experimental study of central effects of adrenochrome. Journal of Neuropsychiatry, 5:33-50.
28. Hawley MD, Tatawawdi SV, Pietavski S, Adams RN. (1967) Electrochemical studies of the oxidation pathways of catecholamines. Journal of the American Chemical Society, 89:447-450.
29. Hirsch EC. (1994) Biochemistry of Parkinson’s disease with special reference to the dopaminergic systems. Molecular Neurobiology, 9:135-142.
30. Hoffer A, Osmond H, Smythies JR. (1954) Schizophrenia. A new approach. Part II. Journal of Mental Science, 100:29-45.
31. Koenig J, Edwardson J. (1997) Endocytosis and recycling of G-protein-coupled receptors. Trends in Pharmacological Sciences, 18:276-287.
32. Koppenol WH. (1998) The basic chemistry of nitrogen monoxide and peroxynitrite. Free Radical Biology and Medicine, 25:385-389.
33. Korytowski, W. Sarna, T. and Zareba, M. (1995) Antioxidant effect of neuromelanin. The mechanism of inhibitory effect on lipid peroxidation. Archives of Biochemistry and Biophysics, 319:142-148.
34. Kötter R. (1994) Postsynaptic integration of glutamatergic and dopaminergic signals in the striatum. Progress in Neurobiology, 44:163-196.
35. Kunugi H, Nanko S, Weki A et al. (1997) High and low activity alleles of catechol-O-methyltransferase gene: ethnic differences and possible association with Parkinson’s disease. Neuroscence Letters, 221:202-204.
36. Lan J, Jiang DH. (1997) Excessive iron accumulation in the brain: a possible potential risk for neurodegeneration in Parkinson’s disease. Journal of Neural Transmission, 104:649-660.
37. Lerengle B, Faucheux BA, Bouras C, Nillesse N, Spik G, Hirsch EC, Agid Y, Hof PR. (1996) Cellular distribution of iron-binding protein lactotransferrin in the mesencephlon of Parkinson’s disease cases. Acta Neuropatholica, 91:566-572.
38. Liang CT, Sacktor B. (1978) The stimulation by catecholamines of guanylate cyclase activity in a cell-free ststem. Journal of Cyclic Nucleotide Research, 4:97-111.
39. Liu J, Mori A. (1993) Monoamine metabolism provides an antioxidant defense in the brain against oxidant- and free radical-induced damage. Archives of Biochemistry and Biophysics, 302:118-127.
40. Marder K, Logroscino G, Tang MX, Graziano J, Cote L, louis E, Alfano B, Mejia H, Slavkovich V, Mayeux R. (1998) Systemic iron metabolism and mortality from Parkinson’s disease. Neurology, 50:1138-1140.
41. Mattammal MB, Strong R, Lakshmi VM, Chung HD, Stevenson AH. (1995) Prostaglandid H synthase-mediated metabolism of dopamine: implication for Parkinson’s disease. Journal of Neurochemistry, 64:1645-1654.
42. Matthews SB, Henderson AH, Campbell AK. (1985) The adrenochrome pathway: the major route for adrenalin catabolism by polymorphonuclear leucocytes. Journal of Molecular and Cellular Cardiology, 17:339-348.
43. Montine TJ, Fanis DB, Graham DG. (1995) Covalent crosslinking of neurofilament proteins by oxidized catechols as a potential mechanism of Lewy body formation. Journal of Neuropathology and Experimental Neurology, 54:311-319.
44. Mumby S, Koizumi M, Taniguchi N, Gutteridge JMC. (1998) Reactive iron species in biological fluids activate the iron-sulphur cluster of aconitase. Biochimica et Biophysica Acta, 1380:102-108.
45. Muthane U, Yasha TC, Shankar SK. (1998) Low numbers and no loss of melanized nigral neurons with increasing age in normal human brains in India. Annals of Neurology, 43:283-287.
46. Napolitano A, Palumbo A, Misuraca G, Prota, G. (1993) Inhibitory effect of melanin precursors on arachidonic acid peroxidation. Biochimica et Biophysica Acta, 1168:175-180.
47. Nirenberg MJ, Chan J, Vaughan RA, Uhl GR, Kuhar MJ, Pickel VM. (1997) Immunogold localization of the dopamine transporter: an ultrastructural study of the rat ventral tegmental area. Journal of Neuroscience, 17:4037-4044.
48. Nishibayshi S, Asanuma M, Kohno M, Gómez-Vargas N, Ogawa N. (1996) Scavenging effects of doamine agonists on nitric oxide radicals. Journal of Neurochemistry, 67:2208-2211.
49. Odh G, Carstam R, Paulson J, Wittbjen A, Rosengren E, Rorsman, H. (1994) Neuromelanin of the human substantia nigra: a mixed type melanin. Journal of Neurochemistry, 62:2030-2036.
50. Pearce RKB, Owen A, Daniel S, Jenner P, Marsden CD. (1997) Alterations in the distribution of glutathione in the substantia nigra in Parkinson’s disease. Journal of Neural Transmission, 104:661-677.
51. Quartz SR, Sejnowski TJ. (1997) The neural basis of cognitive development: a constructivist manifesto. Behavioral and Brain Sciences, 20:537-556.
52. Razdan S, Kaul RL, Motta A, Karl S, Bhatt RK. (1994) Prevalence and pattern of major neurological disorders in rural Kashmir (India) in 1986. Neuroepidemiology, 13:113-119.
53. Saper CB, Petito CK. (1982) Correspondence of melanin-pigmented neurons in human brain with A1-A14 catecholaminergic groups. Brain, 105:87-101.
54. Schipper HM, Liberman A, Stopa EG. (1998) Neural heme oxygenase-1 expression in ideopathic Parkinson’s disease. Experimental Neurology, 150:60-68.
55. Schwartz BE, Sem-Jacobsen C, Petersen MC. (1956a) Effects of mescaline, LSD-25 and adrenochrome on depths electrograms in man. Archives of Neurology and Psychiatry, 75:579-587.
56. Schwartz BE, Wakim KG, Bickford R. (1956bB) ehavioral and electroencephalographic effects of hallucinogenic drugs: changes in cats on intraventricular injection. Archives of Neurology and Psychiatry, 75:83-90.
57. Segura-Aguilar J. (1996) Peroxidase activity of liver microsomal vitamin D 25-hydrolase and cytochrome P450 1A2 catalyzes 25-hydroxylation of vitamin D3 and oxidation of dopamine to aminochrome. Biochemical and Molecular Medicine, 58:122-129.
58. Segura-Aguilar J. (1998) personal communication.
59. Segura-Aguilar J, Metodiewa D, Welch C. (1998) Metabolic activation of dopamine o-quinones to o-semiquinones by NADPH cytochrome P450 reductase may play an important role in oxidative stress and apoptotic effects. Biochimica et Biophysica Acta, 1381:1-6.
60. Shen X-M, Xia B, Wrona MZ, Dryhurst G. (1996) Synthesis, redox properties,, in vivo formation, and neurobehavioral effects N-acetylcysteinyl conjugates of dopamine: possible metabolites of relevance to Parkinson’s disease. Chemical Research and Toxicology, 9:1117-1126.
61. Smythies JR. (1997) The biochemical basis of synaptic plasticity and neurocomputation: a new theory. Proceedings of the Royal Society. London B, 264:575-579.
62. Smythies JR. (1999) Hallucinogenic Drugs. in The Encyclopedia of Neuroscience. G.Adelman, ed. in the press.
63. Solano P. (1998) personal communication.
64. Sulzer D, Joyce MP, Lin L, Geldwert D, Haber SN, Hattori T, Rayport S. (1998) Dopamine neurons make glutamatergic synapses in vitro. Journal of Neuroscience, 18:4588-4602.
65. Taborsky RG. (1968) Indoxyl derivatives: potential psychotropic metabolites. International Journal of Neuropharmacology, 7:483-486.
66. Taubman G, Jantz H. (1957) Untersuchung über die dem adrenochrom zugeschrieben psychotoxischen wirkungen. Nervenartz, 28:485-488.
67. Toffa S, Kunikowska GM, Zeng B-Y, Jenner P, Marsden CD. (1997) Glutathione depletion in rat brain does not cause nigrostriatal pathway degeneration. Journal of Neural Transmission, 104:67-75.
68. Urabe K., Aroca, P., Katsuhiko, T., Mascagna D., Palumbo, A., Prota, G. and Hearing, V.J. (1994) The inherent toxicity of melanin precursors: a revision. Biochemica et Biophysica Acta, 1221:272-278.
69. White HL, Wu JC. (1975) Properties of catechol O-methyl transferase from brain and liver of rat and human. Biochemical Journal, 145:135-143.
70. Zhang F, Dryhurst G. (1994) Effects of l-cysteine on the oxidation chemistry of dopamine: new reaction pathways of potential relevance to ideopathic Parkinson’s disease. Journal of Medicinal Chemistry, 37:1084-1098.

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