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Brian Collins wrote: <<<<For Ron Vetter, copy to Ron Reiner Hello all, and hello Ron Vetter. Thanks for the long email, which I will try to answer. First: How do I know what happens to a normal person taking a large dose of Sinemet :- Because my friendly neuroologist at Nottingham U told me so. He did not gove me a bunch of references, but I have a high regard for his knowledge, and if he says it is so, that's good enough for me. (To expand on 'virtually nothing' : What he actually said was "They might get a slight headache, but apart from that, nothing happens.">>>>>>>>>> rv response: Depending upon how large, this is quite consistent with the lack of much response other than nausea or vomiting with the healthy volunteers in pre-approval testing (no mention of effect) and those who get no benefit (non-PD per se diseases). <<Second: I am quite sure that there is no difference between normal people and PWPS all the way from the stomach to the brain side of the blood-brain barrier. Thus the hypothetical 'large tablet' that I refer to must arrive in the brain, in=A0exactly the same quantity and format in either case. This is a fundamental point about PD - we are just like everyone else, apart from our inability to produce Dopamine. Third: Your description of the dopamine being held in containers at the synapses - available to be released to cross the nerve-to-nerve gap is not quite right: I refer you to pages 26 to 30 of 'The Parkinson's Handbook' (McGoon) and especially p.28. The 'message' that is so important to us is an electrical charge, not a chemical one. The charge can only cross the gap from one axon to the next if the conductive properties of the fluid bathing the axon are favourable, and this depends on the quantity and quality of the Dopamine which the axon receives.>>>>>>>>>>>>>>> rv response: As Dr. McGoon states, he is an amateur: "... how it all functions remains a complex tantalizing puzzle. Even we nonexperts can appreciate that the effort to understand processes that can take place only in a living human brain ..." The doctor mentions the passing of a baton from one runner to the next on page 28. The figure 4 detail on page 29 shows the synaptic vesicles. Unfortunately, he does not state well that the electron charge must be carried across the synapse "on" or "by" the chemical neurotransmitters stored-available in those vesicles. The recipient dendrite receptors must accept the charge carrier - which requires that it fit into a "socket" to transfer the "charge". Then, the dopamine drifts off again into the fluid - without "charge" ... it may be re-stored to the vesicle-storage if levo-deprenyl is present to suppress the normal metabolic destruction. I recommend the article, Anatomy of the Basal Ganglia by John B. Penney, Jr.,M.D., stating on page 8 of the United Parkinson Foundation 1994 Newsletter #1, Part 1. There are also some video documentary illustrations which depict the artist-conceptions neural signalling processes. There are fast electronic signals from dendrite to cell to axon-synapse(s) and the slower chemical transmitting at the synapses via multiple ionized neurotransmitters typically. Some signals to some neurons produce a virtual rain of neurotransmitters from many axons to many synapses. Sometimes to provide a general alert - fight or flight response to perceived hazard. Gone awry, this is a panic attack. Or, a sudden mood change.*********** <<<So the nerve cells in the Substantia Nigra manufacture Dopamine, which travels down the axon to the next nerve cell, where it bathes the synapse.>> rv response: I do not believe the dopamine travels down the axon.******** <<The Dopamine is not the message, and the time at which this process occurs is not necessarily related to the timing of the action represented by the electrical impulse. All that matters is that when the electrical charge passes from the brain to the muscle, the axons which it encounters must previously have been bathed by the appropriate neurotransmitter. What follows is my personal speculation, so don't blame Dr McGoon: It occurs to me that as the electrical charge zips down the axons, encountering synapses along the way ( like points in a railroad track), it may be just as important that certain synapses are 'dry' and do not propagate the signal any further. This may be how dyskinesias occur: through excess levodopa bathing the wrong synapses. Don't forget that in my vision of the whole thing, an excess of Dopamine cannot exist in a normal brain.>>>>> rv response: The electrical monitoring probes recordings during insertions indicate that dyskinesia is characterized by overload-noise signalling in the target site(s) for pallidotomy, thalamotomy, or sib-thalamic locus for stimulator implantatation. The lesioning kills the axon of these cells transmitting so much static or uncontrolled signalling (which is the source of the muscle twitching-tremor or the constant tonus, or the choreic dyskinesia. The dopamine that is missing is from the substantia nigra cells which shut down these overactive transmitters - as I understand the process. Hope this helps. Best wishes from ron -- ron 1936, dz PD 1984 Ridgecrest, California Ronald F. Vetter <[log in to unmask]> http://www.ridgecrest.ca.us/~rfvetter