The American Osteopathic Academy of Addiction Medicine is pleased to present the next iteration in the Essentials of Addiction Medicine. This topic is the Neurobiology of Addiction. A disclaimer at this point is indicated. This is a very complicated topic, and this presentation will cover, just as the name of this series indicates, only the essentials, a stratospheric understanding and view of this topic. My name is Dr. Gregory Landy, and I will be your narrator throughout this presentation. As the narrator of this particular slide set, I have no disclosures to disclose. It is important at this point in time to give credit to Dr. Stephen Wyatt, a senior member of the American Osteopathic Academy of Addiction Medicine, for assembling this slide set, which of course makes the narration of it so much easier. Now I'm of the opinion that it's always useful to start with the most basic information. In this slide, ask the question, what is an addiction? And with that simplicity in mind, let's take a moment to answer that question. An addiction is a compulsion to seek and take a drug. In doing so, the individual, in time, which varies, will lose control. They will no longer be able to limit the amount of drug that they take. Now as a consequence of that loss of control, there will be certain behavioral manifestations that develop. Negative emotional states will develop when access to the drug is prevented, craving independence. And an addiction also is characterized as a relapsing disorder, one that ebbs and flows. And those roots are deeply planted in terms of impulsivity and compulsivity. And as the title of this particular presentation discloses and indicates, there are complex neurobiological mechanisms that emerge and change as an individual moves from one domain to the next, and in time, become deeply ingrained. This slide, in a rather systematic and simple way, sets forth the basic principles of addiction. It's a bio-behavioral paradigm that begins with a cue. Behavioral cues are many, and could include such simple things as watching a TV program and being reminded of an event, walking down the street and seeing an individual in a neighborhood that is reminiscent of drug use, or it could be simply a memory of an individual's past experience with a particular drug. That behavioral cue sets in motion a cascade of neurobiological events that begins with the amygdala telling dopamine neurons in the ventral tegmental area that something good is about to happen. As a consequence of that first step in a very complex cascade, the ventral tegmental area triggers dopamine in the nucleus accumbens to get the drug in the first of many reinforcing steps. As a consequence of the dopamine release in the nucleus accumbens, the individual experiences a substantial reward, a pleasurable feeling that again reinforces the process. As the drug is obtained and ingested, which in a circular fashion leads to an even bigger reward. As this process unfolds, the prefrontal cortex in a neurobiological sense then debates whether to relieve the craving or not. And as we know, when addiction is firmly in place, relief of the craving is paramount. Let's take a look at another definition of addiction, which incorporates and embodies the biobehavioral elements that we just discussed. ASAM's definition of addiction incorporates these complex elements into a comprehensive and unified concept of addiction. As this definition of addiction is noted, it's a primary chronic disease of brain reward, motivation, and memory, and the related neurobiological circuitry. In that simple definition, that simple sentence, we have the essence of the biobehavioral model of addiction. But let's go a bit further. This definition of addiction also considers that there is an impairment in behavioral control, there is craving, and there's diminished recognition of the problems that are associated with the loss of control and the dominance the use of the drug assumes in an individual's interpersonal relationships. And the subsequent dysfunctional emotional responses. And finally, returning to the focus of this presentation, there's dysfunction in these neural circuits that leads to the characteristic biological, psychological, social, and spiritual manifestations that ultimately lead to what we define as addiction. So what causes addiction? Well, there is no simple answer to that question, but it is the focus and the life work of many researchers. From the broadest perspective, we can think of addiction as being the result of two factors, half genetic, half environmental. The genetic correlates of addiction are the subject of research that has explored many interesting polymorphisms, such as the alpha-118G, that seem to have significant associations among cohorts of individuals that have a higher susceptibility of addiction to certain classes of drugs or alcohol. This is an ongoing area of research and is beyond the scope of this presentation, but it's one that's very interesting. And as this area gets better defined in the coming years, it's expected it will have an increasingly significant role in clinical practice. The other cause of addiction, again from the broadest perspective, involves environmental factors. And these could involve impaired resiliency through parenting or life experiences. And it's also interesting to note, and of course DSM-5 emphasizes the role of assessment of culture in our clinical histories. But cultures have different experiences in how addiction is realized in their populations. And so it is interesting to note that the way a culture accepts or does not accept drugs and alcohol can have an influence on that particular population's susceptibility, which again speaks to environmental factors. There are many complicated neurobiological components involved in our understanding of the addictions process. Of course, this is an area of active research. And it behooves clinicians to keep aware of the changes, since in time they will affect clinical practice. For purposes of this presentation, we're going to focus on what is sometimes referred to as the reflective reward system, or in other terms, more of a top-down approach that begins with the prefrontal cortex impacting the nucleus accumbens. This particular circuitry regulates impulses, motions, and helps analyze situations that individuals confront in their environment. This reward system also controls what reactive reward system is triggering, what affects it, and how significantly it's being affected. Now let's take a deeper dive from a neurobiologic perspective in understanding the stages of the addiction cycle. As I continue my narration, carefully study this slide. It's the clue to understanding how this works. So during intoxication, drug-induced activation of the brain's reward regions, which are listed in blue on this particular slide, is enhanced by conditioned cues in areas of increased sensitization, which is reflected with the green shading on this slide. Now during withdrawal, the activation of brain regions involved in emotions, which are listed in pink colors on this slide, results in negative mood and enhanced sensitivity to stress. And during preoccupation, the decreased function of the prefrontal cortex leads to an inability to balance the strong desire for the drug with the will, with the effort to abstain, which in turn triggers relapse and reinitiates this vicious cycle of addiction. The compromised neurocircuitry reflects the disruption of the dopamine and glutamate systems and the stress control systems of the brain, which in turn are affected by the corticotropin releasing factor and dynorphin. The behaviors during the three stages of addiction change as a person transitions from drug experimentation to addiction as a function of the progressive neural adaptations that occur in the brain that is being exposed to the drug or alcohol. One of the best ways to understand the neural mechanisms is to have it depicted in colorful graphics, and that's what we have here. So we're looking at the mesolimbic and mesocortical pathways. And let's begin by taking a closer look at the section of the brain with the pathways in colors on the right. So starting at the bottom, we see the niagrostriatal pathway in purple, and you can see the way it's located in the cutaway of the brain. The yellow is the mesocortical pathway, the orange mesolimbic, the red the GABA pathways, and the green the glutamate pathways. And as you look at this complex circuitry, you can see where it interacts with, for example, the nucleus accumbens, the amygdala, hippocampus, caudate, and ventral tegmental area. Now if we look at this from the table on the left, we can look at the behavior and the associated pathways that are involved with the expression of that particular behavior. So when it comes to behavioral rewards, those actions that reinforce particular activities, the neural substrate underlining reward is the mesocortical limbic dopamine pathway. Now if we look at inhibition behaviors, those activities that tend to decline, we're talking about the prefrontal cortex lateral aspect involved with judgment. And in terms of associative learning, here we're talking about the amygdala, and in particular the medial temporal lobe. Now let's take a look at the mesolimbic pathway. This pathway is naturally triggered by events that would be expected to cause dopamine release. These could include pleasurable events, the anticipation or the performance of them, such as enjoying a nice meal. That process, that experience, is mediated by inputs from the brain's own system of transmitters, if you will, such as the endorphins. Anatomides, such as would be stimulated with marijuana. Nicotine through the nicotine acetylcholinergic system. And cocaine and amphetamine through their actions on dopamine. All these cause a release of dopamine. Now what makes drug of abuse so powerful is that they tend to bypass the brain's own neurotransmitters and directly stimulate receptors. So this is an interesting slide. So let's take a little bit of time and explore it in some detail. Drugs of abuse, despite diverse initial actions, produce some common effects on the ventral tegmental area, the VTA as it's listed on the slide, and the nucleus accumbens listed as NAC. Stimulants directly increase dopaminergic transmission in the nucleus accumbens. Opiates do the same, but they do it indirectly. They inhibit GABAergic interneurons in the ventral tegmental area, which in turn disinhibits ventral tegmental area dopamine neurons. Opiates also directly act on opioid receptors on the nucleus accumbens neurons and opioid receptors, such as the D2 dopamine receptors. Signal via GI. Hence, the two mechanisms converge within some nucleus accumbens neurons. The actions of the other drugs remain more conjectural, less understood, and of course, are the subject of research. Nicotine appears to activate ventral tegmental area dopamine neurons directly through a stimulation of the nicotinic cholinergic receptors on those neurons and indirectly through stimulation of its receptors on glutamatergic receptors that innervate those dopamine cells. Now, let's think about alcohol. Alcohol, by promoting GABA receptor function, may inhibit GABAergic terminals in the ventral tegmental area and as a consequence, disinhibit ventral tegmental area dopamine neurons. Alcohol may also inhibit glutamatergic terminals that innervate the nucleus accumbens neurons. Now, there are other mechanisms which are not shown on this slide that are proposed for alcohol. Now, cannabinoid mechanisms are complex and not thoroughly understood, but appear to involve the activation of the cannabinoid CB1 receptors, which are somewhat similar to the D2 in opioid receptors, and they are G-linked receptors. On glutamatergic and GABAergic nerve terminals in the nucleus accumbens and on the nucleus accumbens neurons themselves. Now, phencyclidine is another story, and it may act by inhibiting postsynaptic NMDA, N-methyl-D-aspartate glutamate receptors in the nucleus accumbens. And finally, there's some evidence suggesting that nicotine and alcohol may activate endogenous opioid pathways, and that these and other drugs of abuse, such as opiates, may activate endogenous cannabinoid pathways, although that's not shown on this particular slide. So let's look at the neurochemical substrates for the acute rewarding effects by linking common drugs of abuse with their neurotransmitters and the anatomic sites where those neurotransmitters exert their actions. So with cocaine and amphetamines, fairly straightforward, with the neurotransmitters dopamine and aminobutyric acid exerting their effects on the nucleus accumbens and the amygdala. Opioids work through their opioid peptides, dopamine, and the endocannabinoids as their neurotransmitters to exert their actions on the nucleus accumbens and the ventral tegmental area. Nicotine is interesting. The neurotransmitters involved are dopamine, aminobutyric acid, and the opioid peptides. And the resulting anatomic sites of activity for those neurotransmitters involves the nucleus accumbens, the ventral tegmental area, and the amygdala. Now, delta-9-tetrahydrocannabinol, which is the active agent in marijuana, involves neurotransmitters, including the endocannabinoids, the opioid peptides, and dopamine, which, again, are exerting their influence over the nucleus accumbens and the ventral tegmental area. And finally, alcohol, one of the more complicated, which is involving neurotransmitters such as dopamine, the opioid peptides, amino butyric acid, glutamate, and the endocannabinoids, which exert their influence anatomically in the nucleus accumbens, the ventral tegmental area, and on the amygdala. So what role does willpower play in human addictions? I think it's fair to say that throughout most of recorded human history, and there are certainly vestiges and large pockets of this still existing, it was considered a moral failing to become addicted to alcohol or drugs, and that individuals with strong, resolute characters would not fall prey and become addicted to alcohol or drugs. And so the moral concept of addictions, certainly in human history, holds great sway. And it certainly is seen in many places currently. But how does this square with our emerging understanding of the biological processes involved in addiction medicine? And clearly, as we learn more about the complex interplay between environment and genetics, we begin to see how this is not a simple linear relationship. And certainly, willpower alone is not the answer. So with that in mind, let's take another look at the neurobiological circuitry involved in the reward system. But let's take a look at it this time from a different vantage point, bottom up, as it were. It begins with a motivation, or if you will, a drive, to achieve a pleasure or to avoid pain. Now, the ventral tegmental area is a site of dopamine-rich cell bodies. The nucleus accumbens is where those dopamine neurons project. The amygdala is connected to the ventral tegmental area and the nucleus accumbens. So there's a rewarding input, which produces a phasic dopamine firing in the nucleus accumbens, which is behaviorally perceived as pleasurable or fun, if you will, which then in turn leads to a conditioned reward experience. The nucleus accumbens and the amygdala are intimately intertwined in producing this learning curve. And in turn, the amygdala is also closely intertwined with the ventral tegmental area, which is involved with relevance detection to previous pleasure or, if you will, memory recall. And finally, the amygdala interacts with the nucleus accumbens, and that produces the emotional response, the impulsivity, and the automaticity, which accompanies this particular process. Now, as we've mentioned in previous slides, both drugs and natural rewards activate dopamine in the brain circuitry. Now, if we look at the graphs on the right-hand side of this slide, we see some interesting things going on. Looking at the bottom graph, we see how food increases dopamine release. There's a spike. And then, of course, it trails off. But look at the relationship with amphetamine. Notice how there is such a greater spike in dopamine release, which explains, in some respects, why it is such a reinforcing drug. Now, let's turn our attention to the left-hand slide at the picture of the brain. Now, as noted on this slide, drugs of abuse obviously increase dopamine in the nucleus accumbens. And it is through that process that the various neuro adaptations are created that ultimately result in addiction. And you can also see, once again on this slide, how the nucleus accumbens is projecting into other areas of the brain, such as the ventral tegmental area, substantia nigra, and the frontal cortex. So this slide builds on and amplifies what we were just talking about. Here we see the effects of drugs on dopamine release in terms of time of dopamine released at the nucleus accumbens. So let's start with amphetamine. So what we see with amphetamine is an acute spike that occurs in less than an hour. And then over the next 90 minutes to two hours, it trails off. Now, contrast that with cocaine, which has a slightly delayed peak and a more rounded plateau before it starts trailing off. Nicotine, somewhat similar to amphetamine, interestingly enough, has a peak release of dopamine in the nucleus accumbens in the first roughly 30 minutes. And then in the next hour, it starts trailing off. Morphine follows, as demonstrated in this particular graph, a dose-related response curve. But in all cases, there is not nearly the peak of dopamine released into the nucleus accumbens as we see with amphetamine, cocaine, or nicotine. So clearly, based on the previous slides, dopamine has a central role in the reward mechanism. And we can summarize this by noting that dopamine release in the nucleus accumbens mediates the goodness effects or the pleasurable effects of drugs, the so-called rewarding aspect, while at the same time hijacking the prefrontal cortex, which involves cognitive control, such things as judgment. The opioidergic system, which is the hedonic component, mediates the reinforcing effects of alcohol by indirectly, and let me stress that, indirectly modulating dopamine release and its effects on the nucleus accumbens. So here we have some imaging studies that are exploring how dopamine D2 receptors are lower as a consequence of the misuse of certain substances. So let's take a look at it. And let me ask, which of the four drugs appears to cause the greatest decrease in D2 receptors? Well, let's begin by looking at the top. We see cocaine. We see both a control image and an individual who is addicted to cocaine. Next, methamphetamine. Again, look at the control and compare that to the individual that has a history of misuse of this particular substance. Moving next, alcohol. And lastly, heroin. Look at the control and compare it to an individual that has a history of heroin misuse. Again, which of those four seems to have the greatest loss of D2 receptors? It appears to me that it's heroin. What do you think? This slide helps makes the case that addiction is a disease of the brain, just as other physical diseases affect the tissue function in other diseases. So if we look at the lower half of this slide, we see the difference in heart metabolism in an individual with a diseased heart. You can see the healthy heart and the diseased heart and how they greatly differ in terms of metabolism. And in a similar fashion, looking at the upper half of this slide, we see how brain metabolism is substantially altered in an individual who has a disease and an individual who misuses cocaine. The control on the left, the cocaine abuser on the right, it's a pretty stark difference. So this slide, again, is another graphic representation of how repeated drug use changes the brain's dopaminergic system. So let's focus on the pre- and post-synaptic membranes between these two neurons. So looking on the left, we see how cocaine stimulates the release of dopamine and the dopamine binding to the post-synaptic membrane and producing a behavioral response that's interpreted as pleasurable. Now, compare and contrast that on the right-hand portion of this slide, which is matched up with the diagnostic imaging that we see. In the control, the post-synaptic membrane is intact. But an individual who chronically misuses cocaine has a reduction in their dopamine system, which is then reflected in the image. The bottom line, repeated use of cocaine or other drugs reduces levels of dopamine D2 receptors. Now, let's move away from dopamine and take a look at the mechanism of action of the GABA amino butyric acid A receptor, the GABA A receptor. You can see a picture of it on the right-hand portion of the slide. The GABA A receptor is an ionotropic receptor, and it's ligand-gated ion channel. Activation of the GABA A receptor selectively conducts chloride ions through its central pore, resulting in hyperpolarization or stabilization of the neuron. That results in an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential being transmitted through the rest of that circuit. The GABA A receptor, as the name would certainly suggest, is the binding site for GABA amino butyric acid. Now, there are different allosteric binding sites that modulate the activities, both direct agonists and enhance GABA binding. Now, these different allosteric sites have become the targets of various drugs, such as the benzodiazepines, non-benzodiazepines, barbiturates, alcohol, neuroactive steroids, and the inhaled anesthetics. Addiction is a developmental disease, beginning in adolescence and even childhood. So if you look at this graph, we see the percent in each age group who develop first-time cannabis use disorder. Now, clearly, we're seeing the peak in adolescence. And interestingly enough, this also seems to correlate with brain areas where volumes are smaller in adolescence than young adults, particularly the amygdala and the prefrontal cortex, both critical in judgment, memory, and experiences. This slide, once again, demonstrates how low levels of striatal D2 receptors are associated with drug use and subsequent impaired activity in the frontal brain regions. The frontal brain regions, of course, are critical in executive function. Looking on the right-hand side, we see the difference between a control and a cocaine abuser. Below that, methamphetamine abuser and alcohol, all of which show decreased D2 receptor activity. At this point, it's probably worthwhile to take a moment and look at the mechanism of action for the various medications that are used in opioid use disorders. It begins with an understanding of the terms agonist and antagonist, both of which are illustrated on the left-hand side of this slide. An agonist drug has an active site of similar shape to the endogenous locus of the agonist drug. It has an endogenous ligand, so it binds to the receptor and produces the same effect. Alternatively, an antagonist drug is close enough in shape to bind to the receptor, but not close enough to produce an effect. It also takes up receptor space, and so it the endogenous ligand from binding at that site. So looking at the right-hand side of this slide, we see these mechanisms in terms of the three medications that can be used to help an individual pharmacologically. First of all, we have a full antagonist, which is naloxone, which, again, is close enough in shape to bind to the receptor, but it does not produce any effect. Then we have a partial agonist, which is exemplified by buprenorphine. And finally, we have a full agonist, which is methadone, which, again, is similar enough in shape to the endogenous ligand, so it binds to the site and produces the same or similar effect. Now, as mentioned at the outset of this presentation, the neurobiology of addictive disorders is amazingly complex, but also one of intense research, and it's very interesting. But there are other factors that are contributing to this picture, and no doubt many more that are yet to be discovered. Some of the other secondary factors include underlying biologic deficits that involve the reward system. These could be more genetic factors. There could also be various understood neuroadaptation in the motivational circuitry, which is secondary to repeated use. Other secondary factors to consider, of course, include cognitive and affective disorders, such as major depressive disorders. And then there are environmental factors, such as the role of supports and interpersonal relationships. Exposure to trauma also brings with it another set of both environmental and neurobiological factors that can influence addiction. And then from a more psychological or social standpoint, there can be factors such as distortions in meaning, purpose, and values that can guide an individual's behavior, and also distortions in a person's connections with self, others, and the transcendent that can also be contributors to addictive behaviors. So let's end this presentation on a hopeful note. Addiction can be treated. And here we have images that help support that premise. Partial recovery of brain dopamine transporters and methamphetamine abusers after protracted abstinence. We see what a normal control looks like. We see an individual who has been misusing methamphetamine, who is about one month after detoxification. And then with a lengthier period of abstinence, we see how the brain dopamine transport system is recovering nicely after 14 months of detoxification. So as we end on that positive note about the efficacy of treatment, here are some resources that you may want to explore to further enhance your knowledge on the subject. And as we close out this particular presentation, on behalf of the American Heart Association, on behalf of the American Osteopathic Academy of Addiction Medicine, your narrator, Dr. Gregor Landy, thanks you. And I look forward to your participation in the other presentations on the various essentials of addiction medicine that our organization can provide.

neurobiology of addiction

compulsion

loss of control

relapsing disorder

dopamine

reward processes

adolescence

recovery