The other question then is, with the genetic predisposition, the other risk factors, mental illness, and trauma, and childhood exposures, and the drugs themselves, how does then opiate addiction really develop? So let's talk a little bit about the brain because obviously, addiction really sits in the brain and one key feature of the brain that's important to understand is something called the limbic system or what's being referred to as the reward or pleasure center of the brain. As you can see in this slide, it really sits in the middle of the brain. Here, looking closely at the brain, you see that the reward center or that orange little half-moon, sits very closely to other parts of the brain that have to do with memory, and pain, and emotions. That limbic system is all encompassed in that middle part of the brain that is the oldest part of brains that make us human. That part of the brain is separate from the purple part at the front where judgment sits. That part is what's called the prefrontal cortex. That part of the brain does not fully develop in humans until about age 25. So you can understand why teenagers are so impulsive because their prefrontal cortex and their judgment awareness really hasn't developed fully. That also helps to explain why adolescents are such high risk for problems connected to substance use. The other thing that's important to understand is that that prefrontal cortex and that now purple part of the brain called the reward pathway and the VTA and the nucleus accumbens really aren't important in terms of specific names. But what's important about this slide is to understand that there's a connection. There's a connection between kind of that emotional reward center part and the prefrontal cortex, so that when people experienced some reward that sensation also gets connected to the judgment and awareness area of the brain. Well, how does that happen? That happens if you think about it similarly to how people communicate, brain cells communicate. People have a transmitter. So the person who's speaking words, they get caught by the ear on the receptor and causes that person to act in some way. The language of brain cells are called neurotransmitters. Their receptors, the ears, are actually little receptors on another brain cell. The reward center in the limbic system contains millions and thousands of nerves and many different neurotransmitters. But the one that is common to all substance use disorders is dopamine. As you can see on this slide, dopamine in one cell gets released and sits on the receptors, attaches to the receptors, on another cell. When that happens, that second cell response in some way, it gets activated is what it's called. But the body is smart so it also tries to recycle the dopamine so it doesn't have to keep making new ones. The dopamine part of the brain is one piece of the puzzle and we're going to come back to that in a second. But the other thing that's important to understand about opiate addiction in particular, is that we are all born with an innate opioid receptor system. The purpose of it is to regulate pleasure and pain. The reward center or the dopamine pathway and the dopamine system, works with something called endorphins. So endorphins are kind of our natural opioids. They are what bind to the opioid receptor and cause indirectly a release of dopamine that then makes us feel good. Endorphins go up when we're engaged in pleasurable activities like having sex, or eating good food, or running. The runners' high is really endorphin related dopamine release. But all substances with addictive potential target the reward center and hijack it, they take over that dopamine system. Cocaine does it directly. Cocaine here in green, yellow green dots, binds to that recycling of the dopamine and causes a huge outpouring of dopamine that stays in and combine to those receptors on those other cells and leads to a hyper activation. Heroin, that mimics the endorphins, binds to the opiate receptor. So the heroine here in purple also then more indirectly causes an increase in dopamine in that reward center. Now what you have is a reward center that has really gone haywire. Lots of dopamine leads to unbelievable euphoria or feeling great. Why is that a bad thing? Well, it turns out that it really overwhelmed that natural process for feeling pleasure and the brain remembers that intense pleasure brought about by the drugs. That memory center, if you remember, sat really close by the reward center and they're all kind of in emotional part of the brain. The memories that are laid down and the learning that actually happens,the connections that get made in that reward center between what brought about the pleasurable feeling and the settings in which that pleasurable feeling happened, that's what drives continued use and it's really been implicated in relapse to substances. Then over time, the body really doesn't like being up and down on these short acting very addictive substances. Slowly then changes happen in the shape of the opioid receptors, with chronic prolonged exposure, and those changes actually alter the way that nerve cells in the brain act. Unfortunately, it seems as if those changes may be irreversible, or at least very long-term. That maybe why so many people relapse after they go through withdrawal, or detox, or after years of not using or being in recovery and then something happens, and now all of a sudden they start using again. This also may be where the genetic predispositions come in because if somebody is born with a different functioning endorphin system, then they may be at risk because their nerves, and their receptor systems may not really work all that well to begin with. So that may be also why people who have addiction just can't really quit because addiction changes brain circuits, and the underlying brain circuits actually may be changed even before people get exposed to the substances. So here, what you see is that the prefrontal cortex that control in a non addicted brain, that's pretty big, and people can even drive that happens in the reward system says to go, go. The controller prefrontal cortex is connected well enough to that reward system. It says, "You know what, I don't think this is really all that meaningful for me, and I remember how bad it felt. So I'm not going to go". Whereas in people with an addiction in their brain, that control center that prefrontal cortex may really be underdeveloped or the connection between it, and the reward system that's much deeper down may not be very strong. So in that individual the drive that says go, may really override anything that has to do with the control. The memory of how that felt, that first-time of using, and that dopamine pleasure. That's really what takes over. The one good piece of news is that we do know that people's brains can heal. So over time brains do start to get back to normal functioning. This is a slide that shows you that. So at the top, in bright yellow, and bright lights is a normal looking brain, in someone who has been using cocaine, and has a cocaine use disorder in the middle row who has not been using for 10 days. You see much less yellow bright lights, and a lot more deep purple. But look at that same brain a 100 days later after not using any cocaine, and you see that the bright yellow lights are coming back. So there is hope, and people can recover. The other thing that is implicated in relapse is that people particularly when it comes to opioids, develop something called an opioid withdrawal syndrome over time. That occurs because with chronic exposure to opioids, those receptors, and the cells get used to actually being activated by those opioids, because we have opiate receptors, not just in our brain but in our eyes, and our skin, in our gastrointestinal tract, in our mouths, in many different other places in the body. So what that means over time, is that it can take more, and more opioids to get the same feeling that's called tolerance. But now when suddenly the receptors are empty the cells can't really act the way that they normally would, and withdrawal occurs. That's what's called physical dependence. That's why people feel really ill if they don't have their opioids. So physical dependence is really important to understand because the difference between addiction, and physical dependence is often confused. So physical dependence really is an adaptation of the body to a specific substance. So that when that substance is no longer there a withdrawal syndrome develops. You can relieve those withdrawal symptoms, in total or part by re-administer during the substance. So for substance use disorders withdrawal, and tolerance physical dependence really develop primarily with opioids, alcohol, and benzodiazepines. But addiction, and physical dependence are not the same. There is an overlap as you can see in this slide with the green dots being the dependence part, and the addiction being the red arrows. So certainly people who have an addiction to opioids. Most of the time also will have physical dependence, but people who take opioids for cancer pain for example, and have been taking them at a high enough dose for a long enough period of time, they will go through withdrawal, and develop some tolerance as hallmarks to physical dependence even if they don't have addiction. Because the addiction really is about the cravings that compulsive drive to use, and keep using no matter what happens. But symptoms of opiate withdrawal are not pleasant. So here is a list of all the things that people experience or can experience with opioid withdrawal. They really represent the number of different body areas because that's where all our opioid receptors are. So people describe it as having a really bad case of the flu. So when people have an addiction, and when they're in withdrawal they're not very happy, and that can drive them to continue to use. So in summary, we're all born with an endorphin opioid system that helps us feel pleasure, and regulate pain. But too much opioids, and too much of any addictive substance for that matter taken into the body over stimulates the reward center. With repeated exposure to opioids or other substances the body adapts, so that long-term changes happen to the receptors, and the cells in the brain. Those changes are manifested by tolerance withdrawal, and memory of that over-stimulation, and all of that drive continued drug use.
