Okay, let's get started. So today is the third class in our four class series of movement and movement disorders. Today we're going to focus on one of those places that initiate, maintains and has a lot to do with the movement and a disorder some mutations or pathological changes in those areas that are causing our main movement disorders. And this system is called dopaminergic system. Dopamine system is not only in the basal ganglia. However, the basal ganglia is definitely the major, major place that hosts dopaminergic system. Therefore, today's movement and movement disorder, we are going to discuss dopaminergic system and a basal ganglia function and dysfunction. Now I read your homework, so you have picked several very good papers. I look forward that this evening we're going to have student presentation. By the way, there is a word that you need to change your way of saying that. There are two words. One is, presentation is presentation. I don't know why the hell you always call it pre. In the United States and UK and Europe, we never say pre. Because pre could mean anything. Okay, pre-med. Pre-clinic. So you never say pre, you say presentation. The other one is a laughable mistake. There is a journal called the Precedings of National Academy of Science, right? P-N-A-S. You cannot say it's penis, this is just so laughable, so change that, those two words. Okay, all right. So today our discussion covers a wide range of knowledge and the logic of those investigations. So what I planned for you, is we're going to talk about dopamine, dopamine receptors in the first part. The second one we'll zoom in, in a particular brain region called the basal ganglia. In Chinese [FOREIGN]. We will talk about the anatomy and the histology. We will talk about functional pathways. The third one we will introduce when these things are not doing their job. When there is a dysfunction in parts of the basal ganglia, what would you see? And I picked two movement disorders. One is Huntington's disease, the other one is Parkinson's disease, to introduce to you. It's very nice complementary two diseases. The third one I will cover very, very briefly, the molecular genetics of HD and PD. Those are the best examples of genetics, cell biology, neurocircuitry, disease. So I want to mention some of it to you just to get you excited. Maybe some of you will continue to go on with brain disease movement disorders later on. Finally, the fifth part is, since we learned all these anatomy, histology, electrophysiology, molecular events, and pathways, we want to ask a simple question. Can we utilize these knowledge and make it work for people? Can we develop pharmaceutical or other intervention methods to help those patients? So you can see it's a long list of things that we're going to cover today. All right, let's start with dopamine itself. Like any neural transmitters, dopamine is synthesized. In our body, we have the synthesis pathway passing through TH, that's an enzyme, tyrosine hydroxylase. TH is a rate-limiting enzyme in this pathway, okay. Guys, you don't need to copy everything because I will give you those power points. But if you want to write down a little bit to help you reorganize your thinking, that's fine. All right, so TH starts from tyrosine and cauterises the transition to l-dopa. L-dopa, through AADC, aromatic amino acid decarboxylase. With its catalysis, it goes to dopamine. So that's the synthesis pathway. Now in the brain, L-dopa can penetrate and be absorbed, taken up by cells. And L-dopa through AADC, it makes dopamine. Don't forget every step in this pathway, it can be metabolized. So L-dopa can throw an enzyme COMT be metabolized to 3-OMD. Or it could go through the other two phases, branches, through monoamine oxidase to DOPAC and through COMT to HVA. These are all dopamine metabolites. I want you to sort of remember this figure that we're going to come back to, and then we'll develop our drugs according to this figure and the points that it indicates. All right, as a neurotransmitter, it needs to have a receptor, right? We have glutamate, we have glufor, a receptor. We have all kinds of receptors. It's the same thing with dopamine. Dopamine has several types of receptors. We label them as D1, D2, D3, D4, D5. Now I listed the molecular structure effects on cyclic AMP agonists and antagonists. All these d1 through d5. Question. When you look at this table, if you have to group them, what would you do? Hint, they're two major types of dopamine receptors. Can you take a look at this and tell me how you would group them? >> [INAUDIBLE] >> Very good. According to their intracellular effects on cyclic AMP, we can put them into two groups. Go on please. >> [INAUDIBLE] >> Absolutely right. D1 and D5, these two, they belong to the same group. The net result of activating D1 receptor and D5 receptor is an intercellular increase of cyclic AMP. Whereas D2, D3, D4, they belong to the opposite group. The activation of D2, D3, D4 receptors will actually yield a net decrease of cyclic AMP intracellularly. Cyclic AMP is one of the most important second messengers. It will trigger a slew of intercellular physiological responses at the cellular level. That, we have talked about in biochemistry, I believe, and in cell biology. I would not get into that, but I do want to remind everybody that in different cells, the increase and a decrease of cyclic AMP, they will give you different responses, right, depending on the cells. But suffice to say, D1, D5, these are the two members of the same group. And 2, 3, 4, they are the members of the same group. Now, if you move down the table, you can see I listed agonists and antagonists, through years of research, both academic labs and in pharmaceutical companies, because scientists have accumulated a large number of antagonists and agonists. These are relatively quite specific, and that's not a small measure. Remember, the D1 through D5, structurally they are quite similar. All of them are, seven transmembrane domain receptors, right. So, to find agonists or antagonists that work on very specifically without affecting the other ones, that's a difficult task. Interestingly and fortunately, through years and years of academic research as well as drug development companies, we have accumulated a very good group of agonists and antagonists. So these are powerful reagents, for you to use if you ever become interested in the problem. Where do the dopaminergic projection reside? Like any nervous system neurotransmitter system, you have the cell, you have the axon, the axon goes to somewhere else, right? The beauty of our nervous system is a neuron takes information in, integrate and make a decision. Then it has an output to the next guy. And then this next neuron does the same thing. Integrate and make a decision, move it to the next one. So when we think about any nervous system we talk about projection. So dopaminergic system, it is involved in several physiological processes. It's involved, for example, in the reward circuit. And the reward circuit is so intrinsic to drugs of abuse. I copied a diagram from the book, from Neuron to Brain. By the way, it's a great book. You should read it. It's not a very big, like this. It's basically for entry level, and it's quite simple, very easy to read. To ask people to finish Erik Kandel's Principles of Neural Science, that's a lot to ask. But if you're interested in neural science, finishing from neuron to brain, it's very doable. Very, very doable. I did it, okay. So the dopaminergic projection, it goes like this in the brain. And let me put another view. Let's take a look at synapse first. On this diagram, the top big one is the pre-synaptic terminal of dopaminergic cells. The second part here, that's the receiving end. Right, it has dopamine receptors. So if we look at that, this is a highly simplified diagram of neurotransmission. So you have those vesicles, neurotransmitter vesicles. They are filled, they are transported to the nerve ending, and they are docked right there. Until there's a signal, then membranes fuse together. Neurotransmitters are dumped into the synaptic cleft. And some of them will bind to the receptors on the other cell's membrane, right? And so on, so forth. Now interestingly if you look at the drugs of abuse. All of those drugs, almost all of them are in the dopaminergic transmission process. To name a few. For example, the cocaine. Cocaine, the major drugs of abuse. Cocaine has several ways of function, but the main way is right here. What it does is this drug, it inhibits the reuptake of dopamine. Remember, when our neurotransmitters are released to the synaptic cleft, we need to recollect them. And the recollection are done by two types of cells. One is by itself, one is by the glial cell. So by itself, we have something called dopamine transporter, DAT. It just recollects that because we don't want to waste all these useful materials. Now cocaine blocks that re-uptake. In essence the cocaine allows dopamine to exist longer time in this space with higher concentration. So that's dopamine. And another very, very commonly used drugs of abuse is amphetamine. Amphetamine can block the dopamine transporter at the same time. Ketamine can facilitate the release of dopamine into the synaptic cleft. So it has two modes of action, and so on so forth. You can see lots of these guys are working on either the release or blocking reuptake and so on and so forth. Now I want to mention that L-dopa, in a certain sense, that is a drug itself. As a matter of fact, the side effect of L-dopa could be those addictive behaviors, okay? So that's dopamine system in drugs of abuse. Now I want to step back from the fine structure of synapse to make it bigger. Let's look at the brain structure where this system resides. Dopaminergic projection, if you take a brain and look at that from the sideways, so if you look at this way. That's anterior, that's posterior, you're looking from the sideways. It's a sagittal cut of the brain, you can see that dopamine, they're just cells. The cell bodies are here and here but they project to pretty long distance ones. Okay, overall the three distance measures of dopamine projection, and I listed. One is very long projection, for example, from that A9, all the way to the left. There are very short ones, for example, in our retina, and then in our olfactory bulb, there are dopaminergic cells and the projections are really, really short.
