New Treatments for Movement Disorders. Part 6

Now as a result of this diagram, now you can become quite confused because in the direct system you have two inhibitions back-to-back. Two negatives, as it were, equaling a positive. Oh, how complicated. Let me try to make it simple for you. The net effect of the direct pathway is to dis-inhibit the thalamus. It must be dis-inhibited because dis-inhibit begins with a D. Dis-inhibits the thalamus, specifically. By that argument then, if I’m talking about the indirect pathway, the net effect of the indirect pathway, since it begins with an I, must be to inhibit the thalamus. Specifically the thalamus. That’s the way I remember it. The net effect of the direct pathway, D, is to dis-inhibit the thalamus. The net effect of the indirect pathway is to inhibit the thalamus. Now the gentleman in the third row says, “Well, what about dopamine?” all in due time. Because we have to add a couple of neurotransmitters in here. We have glutamate, we have inhibitory neurotransmitters. I asked this question to the residents, “The major inhibitory neurotransmitter in the central nervous system is … ?” who said glycine? I’ve got this incredible encyclopedic dissertation about glycine as an inhibitory neurotransmitter. Fair enough, it’s important, but it’s GABA. It’s GABA. I mean glycine is very interesting, fascinating. So is nitrous oxide, but … so GABA, they are all GABA-ergic. Now there are some co-transmitters in here too – I might screw this up because I always do – I think it’s substance P and dinorphine in the direct pathway and substance P an encephalon in the indirect pathway. I won’t write those down because it’s in my notes and I always screw those up. I apologize ahead of time. But there are some co-transmitters.
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So now the question becomes, “What about dopamine and dopamine’s projections to the striatum?” Because, after all, it is the nigra striatal projection so we might as well talk about it. Dopamine will project from the substantia nigra pars compacta to the striatum. But it’s getting too complicated, so I’m going to make it a little simpler. So now we are going to talk about the striatum here and we are going to talk about the substantia nigra pars compacta. This arrow will represent the direct pathway and this arrow will represent the indirect pathway. Dopamine projections onto both pathways mediated by different receptor populations. The direct pathway mediated by D1 receptors, which tend to be excitatory, dopamine projection to the indirect pathway at the level of striatum on D2 receptors, which tend to be inhibitory. Thus, in the normal state there is a general tendency to give some juice to the direct pathway and to put the brakes a little bit on the indirect pathway in the normal … (break in tape) In the inhibition of the indirect pathway what net result do we see? Relatively less direct, much more indirect by the model. So what are the bottom line consequences of that? Now we can go to the slides. The net effect of dopamine denervation over the course of time, as I mentioned before, less stimulation of the D1 mediated direct system, less inhibition of the D2 mediated indirect system, and two hot centers. Two hot places; the subthalamic nucleus of Lewy’s and globus pallidus pars interna. So in the early 90’s you see these reports in monkeys, MPTP monkeys. We put a hole in the subthalamic nucleus of an MPTP monkey associated with contralateral hemibody parkinsonism, and lo and behold we improved his parkinsonism. We actually put a hole in there. We also noticed that there was incredible firing rates in the GPI and perhaps this may have theoretical significance. You know when a scientist is writing like that, he is onto something. Sort of like Crick, Francis Crick, and Watson. At the very last paragraph of their page and a half contribution on DNA, “We think this finding may have theoretical and practical implications.” Now they are playing with GPI. Putting holes in GPI. People have been putting holes in GPI for many years, they just didn’t understand what they were doing. Now they think they understand it a little bit better because they see that they can measure the hot activity of motor-related GPI. They put a hole in that area, they see improvement in the cardinal aspect of Parkinson’s disease. How it explains why the dyskinesia’s go away, you’ve got me. How it improves tremor in certain cases, you’ve got me. But this is the operative model of many smart people in the MA group.

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