Vlog Episode 6 - Feeding the Midbrain

First, I want to warn you, this episode is more technical than the ones before it, and a bit longer.

A lot of people argue that active addiction is feeding the midbrain. They argue that when people take drugs, they get a spike of dopamine in the midbrain reward center. I agree, they do. But that's not what I mean by feeding. Taking a drug is like eating a candy bar. (Of course eating a candy bar is taking a drug for some people, but I'm using this metaphorically now.) It's a quick hit of dopamine but no long lasting sustenance. When these people argue that active addiction is feeding the midbrain, they're only half right. Active addiction is the midbrain eating candy. The opposite of eating candy isn't starvation; the opposite of eating candy is eating a healthy meal that can sustain you for a long time. That's good addiction treatment.

For decades though, the gold standard of addiction treatment is medication free treatment. Just treat someone psychosocially until they can stay off of drugs. Don't give them any medication that feeds the midbrain, because the midbrain is the problem. Talk to them until their cortex is strong enough to clamp down on that bad old midbrain and tell it to shut up. That sounds great until you look at how the brain's wired and you realize that the midbrain feeds the cortex. A weakened midbrain leads to a turned down cortex and emergency thinking. We've been doing mostly the opposite of what we should have been doing.

By feeding the midbrain what's good for it, I mean giving it a higher tone of dopamine, not higher spikes. We also want to increase the tone with a method as close to reversing the actual cause as possible. There are many ways to do it, and sometimes we have no specific way to reverse the problem with a patient and we have to raise his dopamine in a general way. You do what you can, but being more specific is better. And so there are a few principles of addiction medicine we can derive from this. 

First, we use long acting agents that preferentially don't start to work fast. When push comes to shove though, if they work for a long time, it's OK if they start fast. It's the fast high followed by a crash that we really want to avoid. The idea here is that we want to raise the dopamine tone in a sustained way. In science that's called tonic as opposed to phasic, the up and down way a drug works. So we're looking for tonic ways to increase dopamine tone. I need to explain a bit about that before I tell you more about what we can do medically. 

Dopamine tone at the nucleus accumbens is made up of three parts: the amount of dopamine released, the number and function of the dopamine receptors, and the amount of time that the dopamine is available to the receptors. So, we could make an equation: dopamine tone varies with released dopamine, the number and function of dopamine receptors, and the amount of time that the dopamine is available to the receptors.

DT ~ RD X DR X T

We can break that down even further, because released dopamine depends on the number of dopamine packets released per second and the number of dopamine molecules in each packet. And the time the dopamine has at the receptor is inversely proportional to the speed of enzymes breaking it down and a re-uptake pump that sucks it back into the cell it came from.

DT ~ D/P X P/Sec X DR X (E+RP)

Luckily, the re-uptake pump accounts for 90% of that so we can ignore the enzymes in the big picture. Now we have a fairly complicated equation there. But it's so helpful.

DT ~ D/P X P/Sec X DR X RP

It tells us where we can intervene medically, which is at every place in this equation except one. The one place we can't medically affect a patient is in the number and function of dopamine receptors, but we'll talk about that one later. So let's go through this equation piece by piece.

Let's say that someone is born who doesn't make enough dopamine. There are such people, and they will have low dopamine per packet. One reason for this is a mutation in an enzyme called MTHFR. The actual name is methylenetetrahydrofolatereductase, but as you can see the abbreviation, you can probably figure out what we call it when we're not on video. Anyway, what MTHFR does is turn the folate you eat as a vitamin to L-methyl folate which is the only form of folate your brain can use to make dopamine. If the enzyme doesn't work right, you don't make enough dopamine no matter how much folate you eat. But the good news is you can eat L-methylfolate directly in pill form and reverse the deficiency. Someone with this mutation who isn't making enough dopamine and has a low dopamine tone, can have their tone raised by taking L-methyl folate. It's pretty fun to watch someone who has never felt OK in their lives suddenly feel OK. 

There's another thing that can effect dopamine per packet. As I mentioned, the dopamine is taken back up for reuse that that reuptake is 90% of ending the dopamine signal. We can ignore the enzymes between the cells. When that dopamine is taken back up it has to travel through the body of the cell to be repackaged, and during that trip it's exposed to another enzyme that we can't ignore. Monoamine Oxidase b, or MAOb. Think of it like a valley through which some deer have to travel. There's a hunter in the valley and he has a single shot rifle. He may get a few of the deer before they get to the end of the valley, but most will get through. The hunter is MAOb. There is a mutation of MAOb that causes the enzyme to run faster than normal. It eats more of the dopamine than it does in most people. That's like the hunter having a machine gun. He stops lots more deer from getting to the other end of the valley, and a mutated MAOb stops lots more dopamine from getting to where it can be packaged for release. This lowers the amount of dopamine per package. What we can do is give a long acting MAOb specific blocker to reverse this effect and raise the dopamine per package.

What if you have a good amount of dopamine per package but you don't release many packages per second? This package release is under the control of a couple of receptors on the Ventral Tegmental Area cells. I'm not going to get into scientific details about this, but we commonly refer to these as the nicotine receptor and the opioid receptor. When you take opioids or nicotine the action of the drugs at these receptors cause a spike in the dopamine packets per second released. And nicotine and most opioids are what are called full agonists. That means they turn the receptor on all the way. We now have medications that are long acting partial agonists at these receptors, so that we can turn on the receptor just part of the way for a sustained period of time. So there's no high and no crash, but just a tonic increase in the number of dopamine packets released per second and, therefore, the amount of dopamine released per second.

So that covers the released dopamine, but even if you make and release enough dopamine, you might still have low dopamine tone. The dopamine is sucked back up by the Ventral Tegmental Area cells via a channel known as the dopamine transporter. It's just a protein that forms a channel through the cell and grabs dopamine to shove it through. You can have a polymorphism in this protein so that it sucks up the dopamine faster. That leads to lower levels of dopamine at the receptor even if you have normal release. And there are drugs that work at this receptor by blocking it and causing a high. There are also drugs that cause the receptor to run in reverse. These also cause a high. And a crash follows an exhausting high; that's how the system works. Luckily, we now have medication that acts, not for minutes, for many hours, that also blocks this reuptake pump and raises dopamine levels.

So you can see what I mean about specificity. If we have someone who has low released dopamine because of MTHFR and we give him buprenorphine, he'll feel better, but that's not as specific as we can get. So we want to use long acting agents as specific as we can be to alter the specific dysfunction the patient has. 

You probably noticed I didn't mention yet about fixing DR. That's because we can't yet on an human outpatient basis, not with medication anyway. But there is something we can do with that and as a segue into how we set up a treatment system, we'll take a look at that next time.