Finding the Brain's Addiction Switch | Steven Laviolette | TEDxWesternU

Addiction is an aspect of the human condition that will likely affect everyone in this room, either directly or indirectly, depending on the personal experiences we have in our lives with

addiction

or the experiences one of our loved ones has with

addiction

. . all kinds of different rationalizations to explain why addictive behaviors occur. Okay, so we can think of addiction as a bad habit. So something we have fallen into due to circumstances in our lives beyond our control may be addiction, it is just a personal choice, it is addiction. It may be a moral failure, it has to do with some type of intrinsic personality defect.

Well, recently we've been thinking about addiction in terms of being a disease state. Now I'm a neuroscientist. I have been studying the neurobiology of addiction for almost 20 years. For years now I have come to appreciate the importance of how we conceptualize addiction because it really addresses how we approach the topic of addiction in terms of our research and in terms of how we treat people who suffer from addiction, now the disease model of addiction. addiction. is probably something everyone in this room is familiar with: think of addiction as an organic

brain

state similar to what we think of as typical

brain

diseases like Parkinson's or Alzheimer's.

Also suggesting that addiction should be considered a permanent state of brain pathology is the idea that once an addict always an addict encapsulates this idea that addiction might be better represented as a disease state, but today I am going to argue that this is probably may not be the best way to address addiction. o think about addiction and I'm going to suggest that there is an alternative way of thinking about addiction rather as a disorder of the reward and memory pathways in the brain. Now some of the implications of this addiction model suggest that addiction is rather a plastic series of brain adaptation it is a dynamic process in the brain rather than a permanent state of brain pathology it is something we can reverse and ultimately decide that addiction It could be controlled by specific molecular mechanisms in the brain that can actually get you out of an unhealthy situation. -From addicted state to addicted state, okay, then the well-known addiction cycle of all drugs of abuse begins by producing very strong rewarding effects.

In my field of study, we analyze the rewarding effects and addictive properties of opiate class drugs, so this includes drugs like heroin, morphine and, more recently, prescription narcotics, and we have had a tsunami of addictions related to drugs like vicodin percocet oxycodone, which have cost us billions of dollars, not to mention the horrendous social cost associated with addiction to these substances now, if we take them. drugs over a prolonged period of time, what happens is that we begin to develop adaptations in our brain, changes in the brain occurred in terms of our neuronal chemistry, the molecular substrates that control these pathways and even structural differences in various regions of the brain , we eventually develop psychological and physiological dependence on the drug after a period of exposure to the drug of abuse now this is especially true with opium class drugs, we have this very strong physiological dependence syndrome that develops with drugs of abuse. the opiate class now, once we are taken off the drug, we are almost inevitably going to go through a period of withdrawal and that is accompanied by these very strong feelings of craving, you have to reintroduce this drug into your system to relieve those withdrawal feelings that you're experiencing now, finally, kind of the fourth part of this chain and that we discussed is actually extremely important and one that has been underestimated for a long time is the importance of memory-induced relapse, so if If I injected heroin right now and experienced these profoundly rewarding effects and then forgot about it in 20 minutes, I probably wouldn't get addicted?

What happens when we experience the rewarding effects of a drug of abuse? Our brain forms associations between those drug effects and all environmental cues. For example, someone who was addicted to heroin and has been clean. for 10 or 15 years, walking down the street, they see some kind of... in their environment that triggers those addiction memories again and they relapse again, so you can see it when we look at it in terms of this chain of events to deal with effectively. In addiction we need to break at least one of these links, so in a nutshell we can think of addiction as being largely controlled by reward systems in the brain and memory systems in the brain, now in terms of explaining addiction based on many years of animal experience. research based on clinical research and there were also two types of general theories about addiction that were quite popular at the time I started this type of research about 15 or 20 years ago, one set of theories were the dopamine reward theories and this was based on the idea that almost all drugs of abuse activate dopamine neurons, this release of dopamine occurs in the brain, so logically we think that good drugs would activate dopamine, that's why I become addicted, we activate our dopamine system and that's why we keep taking it.

Drug theories now on the other side of the spectrum focus more on the darker side of the addiction process and these types of theories suggested that the reason we continue to use drugs of abuse is because we went through the lottery and need to look for discovered those drugs in our environment to alleviate those unpleasant withdrawal feelings we are experiencing, so when you think about these theories for a second, you realize that there are some obvious problems with both in terms of dopamine, just as the years went by. When we realized that dopamine is not as simple as we thought, tomorrow dopamine will be more complicated, so, for example, dopamine is activated even during unpleasant experiences.

The other theory of the problem is that it explains well why we take drugs in the first place, but we know that when we continue to take drugs of abuse, their rewarding effects tend to diminish over time, even the dopamine response can sometimes become increasingly diminished. So how do you explain why we continue taking drugs of abuse for years and years and years? On the abstinence-based side of the equation, theories do a good job of explaining why we relapse into addiction, but they don't do a good job of explaining why we start taking drugs with use in the first place, for example.

So an obvious question is: Is there some kind of link between the brain mechanisms that control these early rewarding effects of drugs and these later effects of withdrawal and I want to present this idea of ​​an addiction shift that can essentially serve as a mechanism to explain the transition from healthy and unhealthy living. -addictive brain state to addictive bracelet we know that addiction fundamentally changes the brain. I talked about a couple of those changes that have been at a molecular level or a chemical level at a structural level and, more importantly, looking beyond the brain, addiction fundamentally changes the cell that changes. your personality changes your cognition, it changes your behavior and anyone who has seen a loved one go through the horrible effects of addiction, one of the things that stands out in your mind is that you remember how much it changes that person's personality and behavior.

While we are under the influence of drugs of abuse now in terms of opiates, one of the most addictive drugs that are potentially available. We knew a couple of important things about opioids that suggested there might be some kind of

switch

ing mechanism between them. that in the naïve state, before becoming addicted to opiates, the effects of opiates could be mediated through a dopamine-independent pathway, so you do not need dopamine to experience the rewarding effects of opiates when you start taking drugs, obviously in the naïve state there is an absence of withdrawal mechanisms in the brain, there are a minimal amount of molecular changes occurring, but then we looked at the effects of the opiates in the addicted state and we saw a profound difference, so first of all we notice that the rewarding effects of opiates, once you are addicted, opiates activate the dopamine system, so you need to

switch

to a dopamine system, there are very strong feelings of withdrawal and craving, obviously, there are alterations deep molecular and several mark reward pathways that are very important, so The question that was posed when I started looking at this question about 15 years ago at the University of Toronto was whether or not we can find this elusive hypothetical switching mechanism in the brain that controls this transition from a non-addictive state to an addicted state.

We say this without going into the details and the years of research that led to these conclusions, what we were able to find was that when we focused on an area of ​​the brain called the neuro ventral tegmental area. Anonymous likes to think of these as unpronounceable words, but we'll just call it VTA for the sake of simplicity. This is an area in the middle part of your brain, kind of the base of your brain and it contains the dopamine system and it's very important for drugs of abuse because almost all drugs of abuse produce their effects through the VTA, So in a very simplified explanation of this, what we found was that the gaba-a receptors, which is a type of inhibitory receptor located in that area of ​​the brain, could actually serve as a molecular switching mechanism between a non-normal state. addicted and in it an addicted state, so the GABA receptor can normally be thought of as controlling the bioelectrical properties of a neuron.

They control whether a neuron is on or off and, surprisingly, what we found was that in the non-addicted state the A gob receptor acted normally, produced inhibitory signals to the neuron, turned off the neurons, but once we looked at an addicted brain, the A GABA receptor's function switched to an excitatory state, so we are essentially looking at a mechanism that controls reward signaling for a non-addictive granting pathway versus a system that is activated in the addicted state and transfers reward signals to through an addiction brain reward pathway, so it's cool, we found this hypothetical switching mechanism in the brain, but remember I said addiction is more than a reward. we also need to experience memory, we are talking about that, memory is a very critical component of addiction, so for example, as I mentioned before, we need to form these associated memories in our brain to continue that cycle of addiction and next we will see an area of ​​the brain called the basal lateral amygdala and then another one of these unpronounceable terms, we'll just call it the VLA.

Now this is an area of ​​the brain located in the temporal lobes and is extremely important to your ability to form associations. memories between the effects of drugs of abuse and their related environmental cues, so we looked at this region of the brain called PLA to see if this could serve as a memory switch between the non-addicted state and what we found was that in non-addicts The brain's ability to form reward memories of opioid addiction depended on a receptor substrate called d1 and modulated a downstream molecule that we're just going to call d, so a naive non-drug-dependent molecular mechanism in the BL controls addiction memories in the naïve state.

We looked at the addicted brain and what we found was that there was a switch between this d1 receptor mechanism to a completely different brain reward mechanism for the formation of addiction memories and now we were dealing with a system that depended on a type of receptor called the d2 receptor and a completely different molecular signaling pathway, both cam kinase 2, again, just like in terms of processing the rewarding effects of drugs of abuse, when we look at the difference between the addictive state and a non-addictive state, The ability to form drug addiction memories is also under the control of a discrete switching mechanism and what's really interesting about this is that we were able to target those molecules in the amygdala and switch the brain from an addicted state to a non-addicted state. addicted, so this is really exciting because to suggest that instead of thinking of addiction as this chronic, permanent, irreversible state, we can actually go to these areas of the brain, we can target these molecular pathways and we can change the brain of a non-addictive state to an addicted state and This really raises the question of the need for us to make a new paradigm to conceptualize what really happens in addiction.

We know that in the non-dependent state we are dealing with a completely different set of molecular and neuroanatomical mechanisms that you control.how you perceive the rewarding effects of a drug like heroin, for example, but once you become addicted to that drug, something changes in your brain, there is a switch, two completely separate molecular and neural systems in the brain that control how you perceive those effective and rewarding drugs. abuse, so this is really thinking about addiction much more in terms of a plastic dynamic process that allows us to go back and forth between these different states, so where do we go from here?

I think one of the most important questions we need to ask ourselves is to go back to the beginning and address the question of whether or not the disease model of addiction has really served us well and I'm going to argue that no, it really hasn't been a effective model for us in terms of our ability to understand what is happening in the brain and, more importantly, in terms of developing effective treatments for addiction, because remember that after many decades and thousands and thousands of articles of research from all types of disciplines, we have yet to develop a truly effective treatment to deal with the devastating effects of addiction.

The problem with the disease model of addiction is twofold. The first problem is that it doesn't take into account these dynamic processes that happen in the brain as you go from a non-addictive state to an addictive state, because I said at the beginning that We think of illnesses as a kind of permanent static. processes rather than these more dynamic switching mechanisms that occur in the brain, the second problem is that when we use a disease model of addiction, whether we are talking about formulating questions for our research or developing more effective cyclical therapies to treat addiction, we tend to focus more on the effects of the addiction, we focus on the symptoms of a dish rather than the underlying causes of the addiction.

Having said that, I think there is enough evidence, Jess, that a better way to think about addictions is that we are dealing with an altered but reversible state of the brain, it is controlled by a series of molecular mechanisms that control the change of a non-addictive state to an addicted state and, as I said before, the most exciting thing about this is that it allows us to enter the objective of the brain. these molecular pathways and potentially developing more effective pharmaceutical therapies or more effective psychotherapeutic approaches to dealing with addiction by appreciating some of these dynamic mechanisms, so, as I said at the beginning, one of the important things about addiction in terms of understanding how processes the rewarding effects. of drugs of abuse is the idea that we can identify a switch and ultimately turn off the effects of addiction in the brain.