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On Wed 21 May, Stephan Schwartz wrote: > TO BRIAN COLLINS: > RE: MODELS FOR PD > I AM NOT COMPLETELY CLEAR ON WHETHER THE > FOLLOWING SHEDS ANY LIGHT ON THE CREATION OF A > FEEDBACK CONTROL MODEL - IT ACTUALLY SEEMS TO > BEG THE QUESTION, WHY DO OVER-RESPONSIVE D2 > RECEPTORS CAUSE TREMORS? ANYHOW: > > SEE "MOTOR RESPONSE COMPLICATIONS AND THE > FUNCTION OF STRIATAL EFFERENT SYSTEMS," > NEUROLOGY 1993: 43:S 23-27. . . . . ALSO REPORTED IN > PARKINSON'S DISEASE UPDATE, #57, 1995. > > "AS PARKINSON'S DISEASE PROGRESSES, NERVE > CELLS IN THE SUBSTANTIA NIGRA CONTINUE TO > DISAPPEAR. . . . THE CELLS ARE NOT NUMEROUS > ENOUGH TO STORE DOPAMINE AND RELEASE IT > GRADUALLY . . . .GLIAL AND ENDOTHELIAL BRAIN > CELLS CONTRIBUTE TO THE PRODUCTION OF > DOPAMINE, BUT THEY CANNOT STORE DOPAMINE, > HENCE THE 'DUMPING' INTO THE SYNAPTIC CLEFT. . . " > [NORMALLY FOLLOWING RECEPTOR STIMULATION, > DOPAMINE IS PUMPED BACK INTO THE NERVE CELL > THAT CREATED IT. WHEN DOPAMINE PERSISTS IN THE > SYNAPTIC CLEFT IT LEADS TO HYPERACTIVITY] > "THERE ARE TWO MAJOR PATHWAYS FROM THE > STRIATUM TO THE INTERNAL GLOBUS PALLIDUS. . . . > THE DIRECT PATHWAY CONNECTS THE GP TO THE > STRIATUM BY MAINLY D1 RECEPTORS. . . . THE > INDIRECT PATHWAY CONNECTS THROUGH THE > EXTERNAL GP AND THE SUBTHALAMIC NUCLEUS. . . . > WITH PARKINSON'S THE D1 NEURONS ARE > UNDER-RESPONSIVE (BECAUSE OF LESS DOPAMINE), > BUT THE D2 NEURONS BECOME OVER-RESPONSIVE. . . > . . THE SUB.TH.NC. & INTERNAL GP BECOME > ABNORMALLY ACTIVATED. . . .SINCE THE GP ACTS LIKE > A BRAKE ON MOTOR ACTIVITY. . . .WITH PARKINSON'S > ITS LIKE TRYING TO DRIVE A CAR WITH THE PARKING > BRAKE ON. . . . PALLIDOTOMY PARTIALLY DESTROYS > THE BRAKE. . . . " > > STEPHAN SCHWARTZ [log in to unmask] > > Hello Stephan, You are certainly giving us some tasty items to chew on. I am not too sure how many of the answers are already known to you, but it is still interesting to speculate. I am specially interested in the picture you paint of the 'return path' for the dopamine. In the model which I built to match my observations of my own reactions to levodopa in varying quantities, I find that there is an optimum rate of flow into the brain which, if you can get it right, produces 'normal' behaviour even in advanced cases such as myself. Now I have np way of knowing whether I am operating with a small number of hyper actiive dopamine receptors, or a larger number of normal ones, but I do know that if I stray by just a small amount , e.g. 10% of the levodopa flow, then I am in an area of dyskinesia which is quite distressing. It seems to me that the dopamine has served all the cells, axons, whatever, and there is a quantity left over. I imagine this left-over amount as rather like a river in flood, and over flowing its banks, spreading into areas and stimulating muscles which we do not want to be stimulated. There is another feature of a flooding river which is relevant: a river usually floods at the same points, and covers the same areas of land, just as in PD, when the dyskinesias occur, it is the same muscles which start acting up. ( I am referring to my personal experience here: Other people will no doubt find different muscles are affected, because (to use the flooded river analogy, the topography of the surrounding landscape is different, so different muscles are triggered, but again always the same for that person. Your mention of the 'Synaptic cleft' as a return path for dopamine interested me , because I wondered if this might be our 'flooded river' - the place where an excess of dopamine has to go, and in the process fires off these semi-random tremors. Another area to speculate on is what happens if you take a really big overdose (e.g. let's say double the minimum requirement, or around 50 mg/hr. A strange thing happens: For some time, it is possible to stay on a sort of plateau with surprisingly small doses of levodopa (less than is needed in the 'ideal' case described earlier, BUT sooner or later you have to come down off that cloud nine, and when you do, the dyskinesias are excrutiating . I think this is what people call End of Dose Dyskinesias, Although I know how to get into the condition, and I know how to avoid it, I could not claim to understand it. Yet again I find the flooded river concept appealing. Do you have any comments ? Returning to your dynamic model for a moment, there must be a lot of areas contributing to this unstable loop; for instance, in my case, I only have tremors when I am conscious. I sleep like a log, not moving all night, and then as I wake, I can feel the tremor starting again. Talking of sleep, I think that is where Ishould be now, so keep the ideas coming! Regards, -- Brian Collins <[log in to unmask]>