We'll be starting the 9 o'clock session on time, so we might have extended time for questions if you start now. Very good. That's great, because we've got a lot of material to cover, and so I'm happy to have a few more minutes. Again, I'm Dr. Steve Wyatt. I'm an addiction psychiatrist located in Charlotte, North Carolina, and this morning I'm going to talk about genetic and neurobiological understanding of addiction. Actually went through my bio, but I actually went to the Chicago College of Osteopathic Medicine, and I practiced emergency medicine for a dozen years before going into psychiatry. I then very quickly identified addiction as an area of interest and went on to do an addiction psychiatry fellowship at Yale, which really launched me into a variety of great things in terms of teaching and being involved in various grants and opportunities over the years. I've been in North Carolina for the last six years. I have no disclosures. This morning I'm going to try to help you understand the interplay between conscious behavior and stimulus response, and I'm going to go into that obviously in more detail, but that's a real key to understanding particularly what we're trying to do in treatment, which you're going to hear about a lot over the next two days of presentations, and try to understand the importance of genetic underpinnings to the development of the severity of alcohol and other drug use disorders, and to understand the basic neurobiology of addiction. It's always hard to tell what might be on a test, but I think to have this basic understanding, and some of it gets rather detailed, it can be very helpful in thinking through questions that you might be confronted with. Addiction is defined as a chronic disease, and chronic in the neurobiologic changes that take place. It's a relapsing disorder, which quite honestly is most diseases other than infectious diseases, but almost really all the chronic diseases will have periods of relapse. In part, how people are adhering to treatment protocols and just changes in their development, but it's characterized by compulsive drug seeking, which is hugely important in what we're going to talk about. That is, it certainly has the potential for causing a response to the drug, but it's really seeking the drug and the adverse consequences that are in place, and people continue to seek drug. It's considered a brain disorder because it involves changes in brain circuitry involved in this reward, stress, self-control, and those changes can last a long time, even after a person stops taking drugs. In this presentation, the term addiction is equated to both moderate and severe substance use disorders, according to the DSM-5. This was, I thought, a very apt quote from Viktor Frankl, that between stimulus and response, there's a space. In that space is our power to choose our response. In our response lies our growth and our freedom. Again, if you think about what we do in treatment, we're trying to increase that space so people have an opportunity to be able to say, no, I don't want to go back to that path. I don't want to take that next drink or use that next drug, but they have to have some ability to be able to have that moment, to have that thought. I will say that much of this presentation, or a number of these ideas, were presented in an article by Nora Volkow and Dr. Boehler with the National Institute of Drug Abuse. The relationship then between cognitive, that is, thinking through what's going on, and the visceral influences, that's the biologic drive that one experiences, has a couple of different ... We need to think about both of these as we consider what is addiction and how are we going to help people that have addictive problems. First of all is, I'll say, the cognitive axis. This fluctuates between perceptions and intuitions, emotions, and it tends to operate quickly and effortlessly automatically. Those are the things that we've learned, we know how to do, we can do them very rapidly and easily. The second part of this system is a more critical or in-depth reasoning. We stop for a moment and we think through it as opposed to a rapid response. It's more effortful and deliberate. Then we have the visceral axis, which is placed in this range between cold and hot. That is the extremes of our behavior, and those extremes include things like hunger and thirst and sexual drive ... I'm not sure why that's happening. It exerts its effects on the cognitive operation, so it pushes that to move in one way or another, and that, again, is what many of us have heard around addictions. I didn't want to do that, but I just found myself stopping at the liquor store or whatever. These visceral influences are the driving force between the urges of hunger, thirst, and pain, sexual arousal. We can all, all of us, have been in these situations that we didn't want to do something, but we just felt this drive to eat something that we weren't going to eat, or call an old girlfriend or boyfriend and that sort of thing when we just knew that wasn't a good idea. The immediate satisfaction of these influences really explains why people will make unhealthy choices. This is all tied up in various brain regions, so it's not a single area. A lot of people think about the nucleus accumbens is where this all is, and that's just ... that's not true. This is a complex system, and it starts within the midbrain, which includes the ventral tegmental area, which is the primary source of dopamine in the brain, and into the substantia nigra, where it's involved in treatment. The basal ganglia, this ventral striatum, that includes the nucleus accumbens, so this is the ventral side of it, and the olfactory bulb, which, interestingly, is the only sense that goes directly into the brain without any sort of moderation of it. Then later, the changes that take place within the basal ganglia include the dorsal striatum, which includes the caudate nucleus and the pitumen and the anterior cingulate gyrus. These are areas of the brain that are more around those changes that take place in cues and environmental response. Then there's the extended amygdala, which is involved in stress. That's the fight or flight response, and that becomes a very important part of changes that take place in the brain over time that result in a person's discomfort when they can't have drug. Then there's also the prefrontal cortex and changes in the prefrontal cortex that result in people having a different salience in the desire for drug. I'll go through these in a little more detail as we go forward. The unconditioned response, when you think about the conditioned response and the unconditioned response, the unconditioned response is that which takes place with the naive individual. You give them a specific drug. These things take place. What is their response to the drug when they first take it? Now it's going to be there to an degree as times go on, but this is the place that we want to take a moment to look at. That is, how does alcohol affect the brain? How do opioids affect the brain, or cannabinoids, nicotine? As you see, they work in various areas, but this is the place where we are looking most closely at the nucleus accumbens, and that is how does it really affect that pleasure experience that one would have in taking a drug, which includes alcohol. One thing that I would point out is that alcohol has an effect on a variety of areas. Not shown here also is the NMDA receptor involving glutamate and its stimulation, but they all eventually get to the nucleus accumbens and result in some form of pleasure. It's that degree of pleasure, which we've all probably heard, that is an indicator of the patient's potential for the development of an addictive disorder. Those people that may have taken opioids for the first time and it lit up their world. I've talked to people that are 30 years old and they'll tell stories of being given robitussin with codeine as a child and it just excited them. It made them feel really great, and others get nauseated and sedated and they didn't like them from the very beginning. It's that sort of response. That's the unconditioned response. Opioids are then influenced over time or modulated over time as a result of continued use of the drug. That results in the development of natural reinforcers and cues. It results in an induction of equivalent or gradual shift in dopamine increases in the brain, how dopamine is affecting the brain. Some of that has to do with downregulation of the novel stimulant, but increases in the cues that are taking place. That's the drive for people to start using or wanting the drug. These cues really can predict the patient's potential for dopamine release and consequently changes in motivation, which I'm going to talk about in a moment. There then is also extensive glutamate adherence projecting to these dopamine neurons from a variety of regions. It's really glutamate that's the ... Glutamate is the primary, the neurotransmitter that is primary in the brain. It drives ... It results in things happening. Dopamine will stimulate it and serotonin to a degree will downregulate it, but dopamine is the driver of our brain in many ways. It's involved in a processing and modulating the response to rewards and conditioned cues. These can be sensory rewards, desire to eat or how we're experiencing our environment. There can be homostatics changes that take place in the hypothalamus that allow us to get on with our lives even though we're putting this intoxicant in our bodies or our brains on a regular basis. It changes what effect the drug has on the nucleus accumbens, so the changes in reward that we're experiencing. Then also emotional responses like in the amygdala or the hippocampus that once again become these almost emotional memories that result in us being in a particular place that just drives a specific response and potential behavior. Then various multimodal changes, particularly in the olfactory, excuse me, the orbital frontal cortex, and that is part of the salience of the attribution of the drug. As you use the drug or the experience of wanting the drug becomes that much more profound. Motivation really is driven by dopamine. I'll read this quote because I think it gets to the core of what I'm going to describe. That is, if by motivation we mean whatever it is that causes someone to follow a particular course of action, then every action is motivated by definition, but in most human behavior the relationship between motives and actions is not simple. It is motivated by a whole chain of events and surrounding conditions. I think that's an important concept in thinking about addiction and why I think understanding that and thinking about that as we meet patients is so important. To not look at they just like to get high and that's all they want to do and they're lazy and that sort of thing that much of the public thinks and that drives the stigma of what's going on, but as specialists to be thinking about what was the motivation, what were all the things, many of which I'm going to talk about in the next few minutes, that really drive their addiction to help us stand back a little bit and think about all the things that result in the motivation that at that moment they make a decision to take a drug again. Motivation begins in the modulation of dopamine in various brain regions, some of which I've just described, and dysregulation of dopamine signaling is associated with abnormal motivation to get drugs and all the known behaviors that result in severe and adverse consequences where they continue to use, even though they've had a heart valve infection and in the hospital for six weeks and they get out and use drug again. What is that? How could they possibly have lost their desire for life in some ways or it's been overcome by their desire for drug? As drug taking becomes the primary motivational drive and arousal and motivation becomes focused on obtaining drug, then there is also withdrawal and apathy to non-drug related activities. Now that's become so prominent that they no longer have the normal response to cues that help them stay alive and function normally in our environment. There's increased brain activation patterns occurring during exposure to conditioned cues and in contrast to these decreases in the prefrontal cortex, there's reported detoxified cocaine users when not stimulated, the prefrontal cortex regions become activated when exposed. What that's saying is that when you put someone that has a cocaine use disorder and take a look at what areas of the brain are being stimulated, there's tremendous stimulation with the cues associated with their drug use compared to those that don't have that response to the cues and there's a down regulation of the actual response to cocaine compared to the person that's naive. So an important area of this is the mesolimbic dopamine pathway and the rewarding and conditioning effects of drugs are predominantly driven by this phasic dopamine cell firing and the release of dopamine, which leads to a large transient dopamine increase in the nucleus accumbens. And that's what's shown in the cartoon here with the profound increase in dopamine release with cocaine and amphetamines. To make note, the Y-axis degrees have changed, but nicotine and morphine, to a degree, are lower. Some of that has to do with the immediate release of the stimulants compared to these other drugs, but it overshadows significantly what would be normal things that we enjoy, good food, exercise, good sex, seeing our children laugh or play, and just taking enjoyment in social interactions. And again, once someone has experienced these profound increases in dopamine release, it can be something that they just, they don't get that release from some of these normal things, and it begins to drive their behavior in a way that they're no longer taking care of them. So there are downstream changes in executive function, seen in addiction that are linked to these changes in tonic dopamine cell firing, and it results in lower but stable dopamine levels. I mean, it evens out over time. And then dopamine reward doesn't equate with hedonic pleasure, but rather ability to encode, prediction of reward, imprinting of incentive value, of reinforcers, so now it's just part of their brain. They, those that are accused, and facilitation of learning of reward associations through this modulation in the subcortical and cortical brain areas. This is a schemata of this drug reward system, and here you see dopamine is blocking the reuptake of, excuse me, cocaine is blocking the reuptake of dopamine in the presynaptic neuron, and just putting profound dopamine into the cell, resulting in a pleasure response in many. And over time, as a result, on the far right, you see the cocaine abuser, user. We try to stay away from abuser and abuse, stigmatic language, but these were downloaded. And, but the, here you see that the number of receptors on the postsynaptic neuron have been downregulated, and that's this modulation of the response to cocaine over time, and that's where you often hear, you know, people will be seeking that first experience that's very difficult to attain after someone has been using drugs for a significant period of time. So this is all part of the reward response and brain imaging studies comparing dopamine increases induced by stimulant drugs as shown in these three photographs, PET scans, and there's marked attenuation of drug-induced dopamine increases in the striatum, which is an area of the brain that, as I said earlier, gets changed over time, that responds to consistent drug-taking, and lower self-reports of drugs' rewarding effects, consequently, are identified relative to non-drug-abusing controls. So they, again, have this change in what's taking place after they've been taking drug for a long period of time, it decreases that, and there's problems in that way. And it lasts for months. These are, we have evidence that these changes are identifiable up to 10 months, and really it's only because the studies were stopped after that, but here it's showing after four months. So the rewarding response becomes deficient in the drug-addicted individuals, and consequently, acute pharmacologic dopamine enhancing effects of the drug can't be explained by themselves as they increase motivation to consume them. They're not getting as much out of it, and we've all heard that. I don't even really like the drug anymore, but there's this profound desire, itch, that needs to be itched to use the drug, and they do that almost unconsciously. It's just very difficult to stay away from that. So it's at that point that they're moving from liking to wanting or needing the drug, and here we see the response to the ventral tegmental area, dopamine neurons to rewarding stimuli, changes with repeated exposure, and dopamine cells fire upon first exposure to the novel reward. The repeated exposure to dopamine causes the neurons to stop firing upon reward consumption. They then fire instead when exposed to the stimuli. That's what really is driving it now, and it's predictive of the reward. That stimuli is predictive of the reward, but they don't get the reward like they once did, and there's a shift in underlying dopamine role in learning and conditioning. Drug-induced phasic dopamine signaling can then trigger neuroadaptations in ancillary circuits that are related to habit formation and behavioral conditioning. That's when we're really moving into compulsive use of drug and the real disorder. So in many ways, to think about, the nucleus accumbens is very much involved in our motivation to do things, but in this regard, it's more around the cues than it is around any reward that they're experiencing. So as we look at all of this and the development of addiction, we see that there's voluntary use and experimentation with drug, which is hugely important, and that's where to try to do preventative work in your community to reduce young people's exposure and desire for drug, wanting to use drug, but then it's the continued drug use that results in gradual impairment in neural function, which then impacts the very capacity to exert free will. Now we have something else that's driving our behavior other than the things that would normally keep us healthy, and that's, I think, just such a profound idea, but there are a variety of things that can result in the trying of drug, which many, many people have drank alcohol, but then it's that response, that initial response, that drives whether they're gonna continue, and those are involved in genetic vulnerabilities, chronic stress, comorbid psychiatric disorders, and all of these factors lead to the potential for automatic and compulsive behaviors such as addiction. So to identify a target between the stimulus and the response is a very important part of how we look at prevention and treatment, but as addiction worsens, it becomes harder and harder to intervene in that place. So just to give you a little bit around some of the genetics, our current understanding indicates that addiction, like many other psychiatric disorders, is a polygenic disease involving a variety of genes impacting the risk for a substance use disorder. So it's not a single gene. It would be nice if it was, but it's a combination. There's many factors that can result in a person's response to drug. Genes likely have an influence, either direct or indirect, on one brain development, and I'm gonna give you an example of that. Excuse me. Relevant neurotransmitter systems and circuitry, drug metabolite pathways, cellular physiology, behavioral patterns, responses to environmental stimuli, and an individual's personality traits. For example, novelty-seeking impulsivity, stress reactivity, really dependent traits are a big driver of, and by dependent traits, I mean dependent on the external environment as opposed to internal stability in some ways. So genetics have a huge play in whether a person is going to develop an addictive disorder. It's considered that between 40 to 50% of the risk has to do with genetics. That response, that experience that one has, along with what is the stability of the individual in terms of recognizing and being able to put some brakes on their drive, which has genetic predisposition. Addictions are, again, around 40%, as shown in this graph, and when you look at things like stroke and Parkinson's, which have far less of a genetic predisposition, obviously, Huntington's disease, 100%, for me, I began to think about, even when I worked in the emergency department, we'd have people with stroke and Parkinson's come in and treat them like they have a bad disease and a problem, and we're gonna try to help them, whereas something like addictions, we so often don't put that as a genetic disorder. We don't see it as something that this individual may very well have had a much more difficult time starting to use drugs and then being able to prevent the evolution into an addictive disorder. Age of onset is also hugely important, and it's associated with this brain development, so the prefrontal cortex is, the prefrontal cortex really governs judgment and decision-making, and it is not fully developed, we don't believe now, until 25 years old, and this is part of the explanation of why teens are prone or susceptible to risk-taking, and some of that is normal development, they're trying things out, it's exciting, they do things that allow them to learn their boundaries and also just expand their skills and their desires, but at the same time, it can involve risky drug-taking, and this can, for those individuals, particularly with a predisposition, result in drug misuse, and it has a strong potential for the development of a drug-use disorder if they start using too early. So risk of drug-dependent problems is significantly greater for adolescent recent-onset users compared to adult recent-onset users, okay? So if someone tries an opiate at 25, 30 years old, now, if they had a strong genetic predisposition, it might, you know, they might take off, and we've all heard that, but other drugs like alcohol or marijuana, they now have this, you know, they maybe have a career or family or have had this ability to have certain development take place that says, yeah, that was fun, but, you know, I've got other things I need to do, I'll use maybe, you know, periodically, but not in excess and on a very regular basis. The lifetime rates of dependence decline from 40% if they start using at 14 years old and have this, you know, genetic predisposition to 10% at 20 years old and older. So every year, there's actually a decrease in the potential for dependence at 14%, you know, averaging, and an 8% reduction in yearly, and this is after 12 years old, in the potential for misuse. So every year that a child goes from 12 to 13 to 13 to 14, 14 to 15, we are, you know, a family, you know, me as a father watched my son not start using at a very early age and knowing these, you know, these statistics is just like one more thing that we keep track of that helps us recognize that the child has less potential of getting into trouble. Not no potential, but less. Another terrible aspect of the development of substance use disorders is severe adverse childhood events, and here we're looking at emotional, physical, sexual abuse, domestic violence, parental use of alcohol and drugs, all in part associated with neglect, and it really puts individuals in lifelong risk for a variety of illnesses, mental health, physical, employment problems, legal difficulties have been linked to this, but five or more ACEs can result in seven to 10 times the likelihood, increased likelihood for a drug use disorder or an addiction. It is profoundly linked to the child feeling unsettled in some ways, and in that way, what I said before about, you know, dependent children, you know, young people with this dependency sort of personalities, the inability to feel settled, the inability to be able to self-soothe is reduced in these young people in a way that sets them up for heart disease and a variety of mental health problems, cancers have been linked to this, all sorts of things, and it's preventable. That's the tragic part of this. So individuals seeking treatment for alcohol use disorders show a high prevalence of these adverse childhood events, and post-traumatic stress disorder, 62% having been victims of childhood, physical, or sexual abuse. Then when we look at brain development, and this is the brain-derived neurotrophic factor involved in maturation of neurons in childhood and adolescence, it's implicated in a whole variety of neuropsychiatric disorders, but a low level of BDNF impedes normal development of serotonin neurons, and there has been specific BDNF genotypes implicated in drug-seeking phenotypes in heroin-dependent individuals. So that is, if they have this, then there is a lower level of normal serotonin neurons, serotonin neurons, which do allow us to feel more settled, and again, many of us have heard this. I just always felt uncomfortable, and the first time I took an opioid, I felt like I was home. I felt like I was one, actually, it was a literature teacher from Texas that I took care of. He talked about feeling he was wrapped in his mother's arms, that the comfort that can come from that, that they hadn't experienced before and needed to be attended to, or they were at risk for drug use disorder. Other examples implicated in neurodevelopment include prenatal nicotine exposure, leading to polymorphisms and upregulation of nicotine and acetylcholine receptors, disturbing the brain maturation and modulators and potential exposure to nicotine and other substance use problems. And this has been contributing to behavioral disorders secondary to altered sensory function and attention. So this really is mom's use of nicotine and looking at long-term developmental problems that can take place, setting a child up for changes that can result in a substance use disorder. And low-level monoamine oxidation alleles associated with reduced volume and function of the anterior cingulate cortex. The anterior cingulate cortex is involved in our interpretation of our environment, and it's very involved in chronic pain, treated with opioids over time, and just that changes where then emotional discomfort, often referred to as pain, is found to need more opioids. And there's this linkage between emotional response and much like physical response and that desire for opioids. But it's a region belonging to one of the main control networks in the brain and can result in susceptibility of substance use disorders. So epigenetics is another aspect in looking at these problems, and it's epigenetics that can modulate the expression of genes and is implicated in neuroplasticity. They can perturb that intercellular level of key proteins, resulting in changes in how the gene is reinforced or how it appears. And this modulation of neurotransmitters signaling both strengthening and blotting can alter formation processing and various neural circuits in the brain that change our reward response, can result in neural functioning in terms of executive functioning and control, interceptive, that is how we are internally responding to our environment and mood and stress reactivity. Modulations of this complex system at multiple interacting levels result in behavioral dysfunctions seen in addiction. Adolescents that are exposed to nicotine result in widespread histone acetylation, promoting gene transcription in the striatum. And again, the striatum is that linkage between the prefrontal cortex and our midbrain where we're, you know, if one had to pick out an area that's more will, it's that place that allows us to have a moment between our desire for something and actually following through on the behavior. There's an upregulation of this phosphate promoting reward and motivation and drug sensitization in the nucleus accumbens and a parallel increase in cocaine's reinforcing effects. This possible molecular mechanism is related to the gateway theory of drug misuse. How is it stimulated? What's the profound interplay between nicotine and drug use? I mean, rarely do we talk to anyone that has a drug use disorder that's not a user of nicotine. And then there's the comp gene, which variants predict prevalence of psychosis in adolescents exposed to cannabis. The comp gene really clears dopamine and other neurotransmitters while we sleep. It's very involved in that mechanism that allows us to kind of reprogram ourselves in a way, get rid of some of the stressors from the day and start the new day feeling better. The impact of the epigenetic modulation on drugs effects and misuse behaviors are evident through cross-fostering, that is, splitting twins into two different households, environmental enrichment, maternal separation, huge and early life adversity, tying into, in many ways, what we see in adverse childhood events. These reward circuits trigger pleasure and relieve distress primarily through dopamine, and it's this balance of reward and anti-reward that starts to take place. Genetic variability in the dopamine system and neurotransmitters that regulate dopamine are seen repeatedly in the addiction phenotype. So it is one consistent pattern seen in a variety of places, but in the phenotype. And dopamine tone and its influence on the type of sensation following first use of the drug is an indicator of potential sustained drug trajectory. Examples of this are dopamine 2R receptors signaling interferes with drug reward while D1 signaling increases it. So polymorphisms resulting in reduced D2 expression linked to increased predispositions to severe alcoholism. What is their sense of reward? And other variations include cocaine variations in the dopamine response, novelty-seeking associated with environmental stimuli, and then again, the comp gene regulation of dopamine in emotional response. What is the ability for the body to down-regulate these things in a way that they're able to not get in trouble? So in the nucleus accumbens, the rewarding effect of drugs are related to increases in dopamine. The nucleus accumbens works on dopamine, and this integrated computation is involved in that hot and cold visceral versus reasoning responses that I talked about in one of the first slides. And it's coordinated output enables drug-directed behaviors. The inability to break the hold of addiction stems from disruptions in many of these functional circuits that we've been talking about. And the inability of addicted individuals to inhibit drug-seeking once craving erupts and the enhanced sensitivity to stress are both obstacles and areas of focus in treatment. And it's really that sensitivity to stress that's way up-regulated in people with drug use disorders that is a primary driver of why they continue to take drugs. That then triggers their motivation to respond to cues and take drugs. So over time, addiction results in neurobiologic changes in the ventral anterior cingulate gyrus or cortex and orbital frontal cortex, both associated with interpretation of craving. On methamphetamine infusion, both cocaine use disorder patients and non-cocaine use disorder patients, it results in increased metabolism in the orbital prefrontal cortex and the anterior cingulate and non-cocaine use disorder in the non-cocaine use disorders, but in the cocaine use disorder patients. So there's changes in the metabolism that take place that are part of this cue response and continued use. Similar changes can be seen in the cocaine use disorder patients, successful in self-inhibiting cravings, and secondary to dopamine receptor sensitivity, drug-dependent patients show arousal when presented with cues. The nucleus accumbens, and here again is that slide I showed you, similar to the one I showed you earlier, but it's that response in the non-dependent patient compared to the dependent patient. The non-dependent patient has a huge response, whereas there's less negative reinforcement, whereas the dependent patient, not nearly the response to dopamine and less significant increase in the changes that result in negative reinforcement. Motivational dependence and emotional memory results in motivational states that are well known to trigger relapse. There are both negative emotional states and drug withdrawal and emotional memories of the protracted abstinence. I mean, it doesn't just go away, and they can contribute to and exacerbate relapse in the evictive cycle. The concept and framework for these changes involves a break in emotional homeostasis termed allostasis that is kind of an up-regulation of what would be the normal response in the extended amygdala, so that stress response is made even worse. In the prefrontal cortex, we have a change in the salience, so we reduce the inhibition and a tremendous increase in salience to the desire for drug and impaired awareness of the illness that could be associated with continued use, and this is all involved in the inhibitory control. From here, it's really this matter of looking at what is the perception, and to just keep in mind that we see the world through our own eyes, and we know the world that way, and for a person to have drug on their brain or these changes take place, they're not saying, oh, I'm only thinking this because I'm intoxicated, no, I'm only feeling this or having this drive because of all the things that I've been talking about, no, that is their perception of life and their needs, and this all ties in then to the potential for relapse, the positive affect that is the drive to use drug, but then the negative is huge, and that's glutaminergic GABA adaptations that result in agitation and depression if they're not using. Their normal response to their environment is downregulated because of that downregulation of dopamine, and this goes on long-term, and it's one of the reasons that we need to look very closely at post-abstinence times and recognize that people are going to struggle because they may not be feeling the joy that one might take with normal, healthy behaviors. All of this then is tied into the development of addiction, that is inhibitory control and executive function, they can't turn it off, memory that's taken place and response and habits that have happened, changes in that reward salience, and once again, salience around the desire for drug, but also the response to cues resulting in motivational changes and uncomfortableness internally, the interceptive changes and aversion in terms of avoidance or stress reactivity, all leads into the potential for addiction, and it's a very complex, it's not a simple disorder. This is a schemata that really ties this together in many ways in that the first use of a drug continued as a reward, continued use, withdrawal, and negative effects, resulting then in this outer circle of stress-reward complex that takes place that results in a variety of neuroadaptive changes that I've been describing to you, resulting then in changes in the response to the drug, but a real desire for the drug, and we just get into this cycle of addiction. This is not in one simple area of the brain. This is why it's so important to be thinking about how we're meeting patients, how we're first introducing ourselves, how our office is set up, to really understand that it is complex and have that empathy, that understanding of the stress that they are experiencing. Have good respect for the patients and just be receptive, be open, learn from them. I've learned so much from my patients, but then have the skill, some of which I'll talk about tomorrow in terms of psychotherapeutic interventions, to be able to do interviews or talk with patients in a way that you can bring out their strengths, have them talking about them in ways that they're able to move forward. Certainly everyone should be doing screening-brief intervention with a potential for referral to treatment, PHQ-9, looking for depression, some anxiety aspects of depression, and then being able to put up or establish a good treatment plan with the patient in mind, individualized, but know the literature, know what might be available, know what medications could help establish a greater period of time between that response and actual activity. How are they going to think through the fact that they're maybe ahead of time, which is what I talk to patients a lot about, not putting yourself in that risky situation. And then just general knowledge of our substance use problems, the prevalence, what to look for in certain situations, certain individuals with certain problems, where is alcohol fitting into that or other drugs? And then other medical and mental health indicators, and just knowing the treatment options. So this is the attitude, skill, and knowledge of really establishing a healthy recovery practice. Treatment can include the things that I've described, including medications, and these are involved in reduction in dopamine, the potential for extinction of the behavior, which is what we use naltrexone for. These are all things that we'll be talking about in the next two days. And then how do they keep from going back into that situation, and that's developing good social supports and attention to good biopsychosocial health. So this brings us back, in many ways, to that idea of understanding the biologic drive of addiction. And some of you that may have seen me speak before, I often use this cartoon, the rider being the conscious mind, has to be prepared for what the elephant needs and wants. Like the elephant is well-watered, well-fed, kept away from elephants of the opposite sex. To be able to drive it in the way that they want to drive it, and that's our preparation for the day, which many of us go through, getting some exercise, eating well, trying to get good sleep. All those things can give us that moment to then be able to live a healthier life. And then the last slide really is this famous slide, I believe, by Tom McClellan, and it really shows this idea that a person has hypertension, you give a specific drug, the blood pressure goes down, you take it away, the blood pressure comes back up, and we say, oh, that treatment works. Whereas in substance use disorders, we so frequently, a patient has a bad substance use problem, we give them, put them in a 28-day program, they do great, they're out of their environment, they're speaking clearly, their brain clears of acute use of drug, but then we send them back into the environment saying, he's cured, and the problem comes back, and we say, treatment doesn't work. And that's not identifying that this is a chronic illness, that we need to be paying attention over time, and really talking to people with regularity about the problem, allowing all these brain functions that I've been describing in the last hour to improve. So, with that, I will thank you, and I'll see you again later this afternoon on The Alcohol Talk.

addiction

genetic underpinnings

neurobiology

brain circuitry

dopamine

nucleus accumbens

substance use disorders

behavioral interventions

personalized treatment