The glutamate-dopamine dual radical connection to neuromelanin
The pigmented neuronal tracts in the brain are involved in the eitology of some neurological and psychiatric disorders. The street drug MTPT was observed to induce neurochemical and clinical changes in humans consuming this compound. D'Amato reported that monkeys receiving pharmacological doses of chloroquine were protected from MTPT induced depletion of dopanine in the striatum. Dammage to the nigral-striatal tract was minimal and the monkeys did not exhibit the parkinsonian motor disorder. A hyperdopaminergic state in mesolimbic and meso-cortical tracts in schizophrenic, but not in normal brains has been reported by Bird et al. Dopamine (D1) receptor blockade by neuroleptics has been reported by Rosengarten to be the receptor primarily involved in the movement disorder tardive dyskinesia. Free radicals have been implicated in tardive dyskinesia (TD), developed in some patients treated by dopaminergic receptor blockade with neuroleptics (Cadet et al, McGinness).
Previous studies of the neuromelanins have emphasized free radical production or elimination, and are concerned with direct tissue dammage. It is the purpose of this paper to present new findings, at the receptor level, which show that both oxygen radicals and nitric oxide radicals are produced. The pathway in Fig. 1 represents the minimal information required to understand how the two neuronal and two radical producing systems interact.
These pathways are modulated by the neurotransmitters dopamine and glutamate, as shown in Fig. 1. Activation of the glutamate receptors results in production of the radical nitric oxide. Oxygen radicals may be produced by catecholamine oxidation or by binding MPTP to neuromelanin. The complexity of these biological interactions is further appreciated when we note that the nitric oxide radicals affect vasodilatation and modulate the cerebral blood flow. I will restrict this review to concepts which bear direct relevance historically or experimentally to Fig. 1 as a more exhaustive review is not possible here. Finally, I will review evidence that the melanins appear to have catalytic capabilities similar to at least two enzyme systems, which needs to be quantitated if we wish to understand how the neuromelanin participates in this system.
The most basic question in our field has been "What is the biological function of melanin ?" Dr Fitzpatrick in 1969 doubted that the answer was purely dermatological, based on the observation that melanin is in the inner ear and brain where not much light is present. As our knowledge of tne physical-electrochemistry of the melanins has evolved, we are discovering that the melanins are not inert waste products.
One of the earliest clinical clues was from the work of Cotzias wha argued for a role for neuromelanin in the etiology of parkinsons disease and was generally ignored, until about 1970 (see Patten for a review), when McGinness and Proctor proposed that melanin could change to cytotoxic under some conditions.
The proposal remained relatively dormant until Proctor and McGinness suggested at the Boston meeting af the Pigment Cell Society, in a symposium question by Dr Riley, that oxygen radicals were involved. The literature which followed concerning melanin and free radicals is too vast to review here. Fortunately it well known to the society. The next result which gained clinical relevance to the eitology of parkinsons disease came when Davis (1979). Lindquist (1983) and others demonstrated melanin binding of a radioactive metabolite of MPTP known to induce parkinsonism. D'Amato (1986) investigated neuromelanin, and (1987) showed that blocking binding to neuromelanin protects dopaminergic neurons.
The next important development was clinical treatment of patients with chronic schizophrenia with venoruton (Casley Smith). Venoruton had been previously shown to ameliorate the toxicity of the oxygen radical producing anticancer agent Adriamycin (McGinness). These reports were published with out reference to free radicals (Casley Smith 1983, 1986).
Free radical mechanisms were introduced independently by Cadet (1987), and McGinness (1987) as a basis for the chronic deterioration seen in chronic schizophrenia. However, normal subjects and schizophrenic patients both have free radical production from neuromelanin and catecholamine oxidation present at all times. What tips the balance ?
One clue may come from the induction of the buccal-lingual movement disorder Tardive Dyskinesia (TD) induced by dopamine receptor blockade. Rosengarten has shown in a rat model that it is probably the D1 receptor rather than the D2 receptor which is primarily involved in TD, by experimentally selectively destroying one population (D1) or the other (D2), in vivo in rats.
His observation is that chronic neuroleptic (D2) blockade chronically exposes D1 receptors to endogenous dopamine. The action of the D2 receptor is to oppose the action of D1. With selective D2 blockade the D1 system can run almost unopposed. No connection with radical production was proposed.
Mechanisms outlined by Ouimet are reviewed in the upper half of Fig.1. The D1 pathway of interest to us is through DARPP32 which through protein phosphatase 1 (not shown) exerts a control on the glutamate receptor. Mattson has recently reviewed the role of glutamate in the regulation of neuronal cytoarchitecture (plasticity), and neuronal degeneration (cell loss). I believe that this may be connected to the neural plasticity hypothesis (Haracz) of schizophrenia.
I propose that the keyb link between radicals and dopamine receptors is Garthwaite's proposal (1988) that the glutamate NMDA receptors use ERDF, the free radical nitric oxide (NO), as a second messenger. NO is further in equilibrium with oxygen radicals which brings us back to neuromelanin. This presents evidence, for the first time that I am aware, that a dual radical population exists in these systems.
I have reviewed the neuro-anatomical literature and find that dopamine and glutamate neurons converge in the striatum, where cell loss has been confirmed (Nielson) after long term treatment with neuroleptics.
The reluctance to accept neuromelanin as biologically active substance was based on its stability. By 1970 many authors were still trying to fragment the material and discover some structural basis for its properties.
We were impressed by the almost total lack of a structural basis for its physical properties and began to investigate its quantum properties.
First its unusual conductivity changes helped to identify it as an amorphous semiconductor, which suggested that a strong coupling might exist between conduction electrons and phonons. Latei Kono measured an anomulously large phonons absorption by melanin and suggested again a strong coupling. Recently, Crippa completed photoacoustic measurements which support decay of excited carriers through phonon collisions (Uppsala. 1989). The ability of melanin to store sufficient energy to run a transistor radio led us to patent these properties and focus on the physical-electrochemistry. Sichel has pursued the capability of liver melanin to mimic the functinn of SOD. Proctor suggests that melanin may evolutionally predate SOD. I noted the release of C02 during titration of melanins but did not realize until recently that they can function as a carbonic anhydrase (nonprotein). Mlelanin appears to be a candidate for a primordial catalysis in nature prior to the evolution of proteins.
In conclusion, efforts to understand the eitologies of clinical disorders involving pigmented neurons have ranged from receptor blockade, or plasticity to free radicals. The pathways outlined in Fig.1 suggest that we are converging on a common theme. Other interactions such as Ca and Cu need to be added, as they become better understood. I appreciate that the information presented here is only a beginning. The objective of this manuscript is to stimulate interest and provide a roadmap through the vast multidisciplinary literature nhich has evolved. The advances which have occured suggest that we may be about to make a quantum leap in our understanding of these disorders.
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John McGinness MD, PhD
Harris County Psychiatric Center
Houston, Texas 77021