How Your Brain’s Reward Circuits Drive Your Choices | Dr. Robert Malenka

Welcome to the Huberman Lab podcast where we discuss science and science based tools for everyday life. I'm Andrew Huberman and I'm a professor of Neurobiology and Ophthalmology at Stanford School of Medicine. Today my guest is Dr. Robert Malenka. Dr. Robert Malenka is a professor of Psychiatry and Behavioral sciences at Stanford University School of Medicine. He is both a medical doctor and MD and and a researcher, a PhD. His laboratory is famous for having discovered some of the key components allowing neuroplasticity, I.e. the nervous system's ability to change in response to experience. In addition, Dr. Malenka's research is considered central to the textbook knowledge about how reward systems in the brain are organized and function. Indeed, Dr. Malenka's research over the last 10 or 15 years has merged what was once two disparate fields. The first being the study of neuroplasticity, again the nervous system's ability to change in response to experience, and the other field being the field of dopamine as it relates to pleasure and addiction. His laboratory has shown, for instance, that when we seek out particular forms of pleasure, regardless of whether or not they are healthy for us, that changes the way that our reward circuitry works and actually changes the way that dopamine is released and how it impacts the brain. And his work has also informed how we seek out healthy pleasures and including healthy food and social connection. Today's discussion explores all of these topics and by the end of today's discussion you will have a rich understanding of how neurochemicals like dopamine and serotonin work in parallel to reinforce that is to increase the probability that we will engage in certain types of thinking and behaviors. So if you are somebody interested in neuroplasticity, that is how the nervous system can change in response to experience and or you are interested in reward systems, what motivates us and what we are likely to pursue in the future, given our choices of past. And if you are interested in things like social connection and empathy, or lack thereof, today's discussion encompasses all of those topics. It is worth mentioning that Dr. Malenka is a true luminary in all of the fields I just mentioned, as well as several other fields. In fact, when you look out on the landscape of modern neuroscience, what you'll discover is that a very large percentage of the top laboratories studying neuroplasticity and reward systems and so on, all stemmed from having trained in Dr. Malenko's laboratory. So it's a real honor and pleasure to be able to host him today. And I'm sure that our discussion is going to greatly enrich the way that you think about brain function, neuroplasticity and reward. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is Roka. Roka makes eyeglasses and sunglasses that are of the absolute highest quality. The company was founded by two all American swimmers from Stanford and everything about Roka eyeglasses and sunglasses were designed with performance in mind. I've spent a lifetime working on the biology of the visual system and I can tell you that your visual system has to contend with an enormous number of challenges in order for you to be able to see clearly. Roca understands those challenges and the biology the visual system such that they've designed sunglasses and eyeglasses that always allow you to see with crystal clarity. Now, initially, Roka eyeglasses and sunglasses were designed for sports performance and as a consequence all of their glasses are designed to be very lightweight and to not slip off your face if you get sweaty. However, the design of the glasses includes some that are specifically for sport and others whose aesthetic really allows you to use them for sport as well as out to dinner or to work, et cetera. And that's how I use them. If you'd like to try Roka eyeglasses and sunglasses, you can go to roka.com that's r O-K-A.com and enter the code huberman to save 20% off your first order. Again, that's roka r oka.com and enter the code Huberman at checkout. Today's episode is also brought to us by levels. Levels is a program that lets you see how different foods and behaviors affect your health by giving you real time feedback on your diet using a continuous glucose monitor. One of the most important factors impacting your immediate and long term health is the way that your body manages its blood glucose, or sometimes referred to as blood sugar levels. To maintain energy and focus throughout the day, you want to keep your blood glucose steady without big spikes or dips. Using Levels, you can monitor how different types of foods and different food combinations, as well as food timing and things like exercise combine to impact your blood glucose levels. I started using Levels a little over a year ago and it gave me a lot of insight into how specific foods were spiking my blood sugar and then leaving me feeling tired for several hours afterwards, as well as how the spacing of exercise and my meals was impacting my overall energy. And in doing so, it really allowed me to optimize how I eat, what I eat when I exercise, and so on, such that my blood glucose levels and energy levels are stable throughout the day. If you're interested in learning more about levels and trying a continuous glucose monitor yourself, go to Levels Link Slash Huberman. Right now, Levels is offering an additional two free months of membership. Again, that's Levels Link L I N K Slash Huberman to get two free months of membership. And now for my discussion with Dr. Robert Malenka. Dr. Malenka, Rob, welcome.

Yeah, thanks for having me.

Delighted to have you here, both for sake of your medical knowledge and training as a psychiatrist and of course as a luminary in the field of neuroplasticity, dopamine and reward systems, social systems, your knowledge of autism and social interactions, a newer interest in, or perhaps old interest in psychedelics and what they're doing, and potential for mental health. There are just so many things that you've done in this field. I've been a long, long time fan of your work since your days as an assistant professor. I've tracked your career. I've learned a tremendous amount from you by observing you and from being your colleague. So really delighted to have you here.

You're making me blush and I don't blush easily.

Well, it's all true. And I will say as well, you've also trained an enormous of incredible scientists. Carl Deisseroth, the Carl Deisseroth. Anna Lemke always speaks incredibly highly of you as a mentor and somebody. She's learned a tremendous amount from and pretty much anyone that's worked on neuroplasticity, on dopamine and reward systems addiction, and now in the fields of autism and soon psychedelics as well. References as you often and you've been mentioned many times before on this podcast, if not by name, by work. So again, thank you for being here. I'd love to kick off the conversation by talking about something which is very fundamental to everything we're going to talk about, but certainly fundamental to our daily lives, which is dopamine. We hear so much about dopamine. People talk about dopamine hits. People think about dopamine as pleasure, dopamine, reward for the novice. How would you frame the dopamine system? I mean, it does a bunch of different things in different areas of the brain. And body. But to you, what does dopamine represent as its major function in the brain? And could you give us a general contour of the neural circuits that allow this chemical to more or less put value on our experiences?

Yeah, that's very well put. As you point out, dopamine is one of the major, what we term neuromodulators in the brain. A chemical signaling messenger that the brain uses to mediate a complex array of actions. Its best well known function is in what we call the brain's reward circuitry. So this is a circuit in the brain. And when we use the term circuit, what we really mean is one part of the brain communicating with another part of the brain. Because the brain is this very complex, it's the most complex organ in the universe with lots of different nerve cells talking to each other simultaneously. And as neuroscientists, we try to parse what different brain areas are doing and what different neuromodulators might be doing. Dopamine was discovered, oh, I should know this many decades ago. It's, as I said, the major chemical messenger molecule in the so called brain's reward circuitry. And when you're talking about, so what is the brain's reward circuitry? This is a part of the brain that tells us something is reinforcing in our environment, some stimuli, or in quotes, is rewarding, makes us feel better or good. Although that's a gross oversimplification. And before getting into the details of dopamine and its function in the reward circuitry, I think it's useful to talk about why do we need a reward circuitry? Why do we need something in our brain that tells us this feels good or this feels bad? And it goes back to evolution. I am a biological scientist. That means I believe in evolution. And if you think about the evolution of our species, everything is driven by developing mechanisms that increase our survival. And it's really useful. You need something in your nervous system that tells you some stimuli in your environment is important for your survival or some stimulus in your environment is dangerous. So it's not magic, that sugary, high fat laden foods are highly reinforcing and rewarding. Rewarding. It's not an accident. There has to be a mechanism in the brain that tells us that it's not an accident. That most of the time, for most of us, a sexual experience is pretty reinforcing, is pretty rewarding. It's not an accident. That warmth feels really good when you're cold, that water tastes much better when you're really Thirsty. There have. What evolved is a mechanism to tell our nervous systems and tell our brains, this feels pretty good. I should repeat the behavior that leads to that rewarding experience. And similarly, it's really important when you, you know, there is an event in your life that's highly dangerous for some mechanism in your brain to say, whoa, I don't want to go back to where that lion was. And we can get into that. So this was a long winded way of saying what the reward circuitry tells us is this event, this stimulus. It could be an external stimulus, like I said, a Krispy Kreme doughnut, which I happen to love, and I have to be very disciplined, so I don't eat too many of them. It could be a drug of abuse, and maybe we'll talk about that a little bit. All of these stimuli seem to activate and cause the release of dopamine in this brain's reward circuitry. So now we need to get into a little bit of detail. Neuroscientists use these very unfriendly terms to describe different brain regions. So the home of dopamine cells or brain cells are called neurons. So the home of dopamine neurons are in a part of the brain, sort of what we call the lower midbrain. The dopamine neurons that are part of the reward circuitry are found in this area called the ventral tegmental area, which I'm sorry to have to use such technical jargon, and we call it the vta. That's the acronym.

The roof of the midbrain is the tectum, it means roof. And the base of the midbrain, it means floor, which is tegmentum. I think that's the. So there's a rationale, but it doesn't help much at all to know the names.

And in fact, you are absolutely correct, and I always forget that. So thank you for pointing that out.

It's a side effect of teaching neuroanatomy.

And then which I once did back in the early 80s, but I've forgotten everything I taught anyhow. So these dopamine neurons, and we can talk about other types of dopamine neurons, they send messages, what we call projections, using telegraph wires that we call axons, they send projections to many different brain regions. The key one in the brain's reward circuitry being an area, again with a very complicated name called the nucleus accumbens. And maybe, Andrew, you know, I actually don't know how that name evolved, the nucleus accumbens. And I'm sure I should know Because I've been studying it for 30 years, but I have never looked up the genesis of that name.

Well, the fortunate thing about this podcast is it's both on audio platforms like Spotify and Apple, but also on YouTube. And so now we can be absolutely sure that somebody has put it into the YouTube comments underneath this episode, and therefore everyone will learn, including us. So I don't know the origins of the word nucleusic, and.

It'S a gross oversimplification, but it's the activity of these dopamine neurons in the ventral tegmental area that then cause the release of this powerful neuromodulated neuromodulator, dopamine, in the nucleus accumbens, which is part of another brain structure with a tough to remember name called the ventral striatum. And then magic happens. And when I say magic happens. Even though we've been studying how dopamine modifies the properties of cells in this nucleus accumbens, the truth is we don't have a deep, mechanistic understanding why when dopamine is released in the nucleus accumbens, we experience that. As I'm being very cautious here, the simple way would be to say as highly rewarding. But it's a little more complicated than that. What it tells us is that there's something really important happening in our environment.

So could we say that it cues.

The arousal system, it gets the arousal system going. There's close ties to our memory systems, which hopefully intuitively makes some sense if something really important is happening in your environment. Because again, I think what's helpful for your audience is to always be thinking about how these systems evolved from an evolutionary perspective. And if dopamine is signaling something really important and salient is happening in your environment, you want to remember that it could be a highly rewarding experience, like a source of food. For me, it's a. I like all donuts. So I don't want to emphasize any one manufacturer of one donut versus the other. I like sugar laden, fat laden foods. That's why I never eat them, because I like them so much. And I use that as an example, but because that was an important event for my survival. This reward circuitry, yes, it stimulates my arousal system. It gets me to pay attention. It also has very close ties to memory systems. And to go off on a little bit of a tangent, I think the one I don't want to say it's a mistake. I think perhaps somewhat oversimplification of how people conceptualize dopamine's role in the brain is, even though it's a major important role, is for it to be active and released during highly reinforcing experiences like sex, like really good food, like drugs of abuse. It also can get activated subdivisions of the system during painful stimuli and during aversive stimuli, which again, are really important for you to be aware of, to say, oh my God, that's really bad for me. And so the dopamine system, this reward circuitry and its subcomponents that maybe perhaps signal more salience or aversion in the environment, are closely tied to arousal systems and memory systems. Again, hopefully for somewhat obvious reasons, you want to remember powerfully reinforcing events in your life, as well as powerfully emotionally or physically painful events in your life. So I hope I answered your question to a modest degree.

No, far better than a modest degree. That's an excellent description of the dopamine system from a true expert. And the question I have is about some of the context and nuance of the system, but in sort of real world terms, how should I think about this? Even in my training as a neuroscientist, I know neurons can be a little active, a lot active, everything in between. They could be active over long periods of time or short periods of time. But let's use the example of the donut. I like a glazed old fashioned donut. I actually don't have a craving for sweet things, but donuts is an exception. I like the glazed old fashioned donut. But if I were to see just a little piece of a glazed old fashioned donut versus a full glazed old fashioned donut, could I expect that more dopamine is released to the anticipation of the complete donut? And then the other question is, how does context influence the dopamine system? For instance, if I'm very full, a glazed old fashioned donut might be aversive to me. Whereas if I'm just a little bit hungry, or if I'm actually more on a schedule of rewarding myself for abstaining from sweet, fatty foods, then abstaining from the food might be its own form of reward. Yeah, I mean, and so to me, the dopamine system seems incredibly simple and yet incredibly prone to immediate context and the kinds of nuance that, I mean, we're constantly juggling. I'll interrupt myself to say that we're constantly juggling a bunch of different reward contingencies. We want to, you know, have good health metrics and maybe have a certain aesthetic qualities to our body, but we also want the donut. And so how does a system as simple as a one neuromodulator system and the VTA to nucleus accumbens, and with some connections to the memory area, how does it balance all of that information in real time? To me, that's just like staggeringly complex, but also incredibly interesting.

I think you beautifully put, very eloquent description. You just said it. It's staggeringly simple, simultaneously staggeringly complex, and you ask several different questions. So context makes an enormous importance. And that's one of the reasons I became interested in the dopamine reward circuitry is, as you know, as a colleague in the academic neuroscience world, but your listeners probably don't. I started out my career studying very basic mechanisms of plasticity. How does the brain modify itself? And what makes the brain different than the computer hardware is the physical connections in the brain are constantly changing the strength of the communication. Similarly for the dopamine reward circuitry, it's highly plastic and it's highly contextually dependent. And so you gave the example of donuts and feeding. And I'll answer your question about it. The cues. Yes, I used to give the example of Thanksgiving. So let me give that example. You know, in the morning of Thanksgiving, all. For most of us in the United States, the morning of Thanksgiving, if you're at home visiting your parents, the smells of the apple pie, the smells of the turkey cooking, are highly appetitive, highly reinforcing. You're anticipating that fun event. You're anticipating Uncle Joe coming to visit you for Thanksgiving. And that's all because these cues, the smells, the anticipation of Uncle Joe's. Your previous experiences are part of your memory system, sort of talking to, in a simple way, your reward circuitry. So you're building up this anticipation, one could almost say this craving, which maybe we'll talk about in the context of addiction. And then to make a long story short, think about that evening at the end of Thanksgiving. Those exact same cues, the exact same smell of the apple pie, turkey, and Uncle Joe himself. At the very least, they're no longer appetitive, meaning they might actually be aversive. The last thing you want is a piece of apple pie. You can't wait for Uncle Joe to leave your Thanksgiving dinner. And I always argue that does not happen magically. That happens because your brain has been modified by the context in which it sits. And this very important modulatory system, this reward circuitry, is responding to the exact same stimuli with a very different response. So that. I'm just telling you, I'm repeating what you said. The Phenomenology. And again, my other favorite example is any of us who have been in an intimate relationship knows that the love of your life can turn to the bane of your existence in 20 seconds. And again, that doesn't happen magically. This person, who you crave, who you love does something and two minutes later, your brain is saying, oh, my God, you know, I may have to break up with this person. Or this is an incredibly painful experience, emotional experience. And what fascinates me about the brain is how does the brain mediate that rapid change? So now back to. So, yes, context is everything about how this powerful neuromodulatory system that uses dopamine works. And the truth is, we don't know. It's because the inputs onto these dopamine neurons, the other nerve cells that are driving the activity of the dopamine neurons. And I've actually studied this in my lab at Stanford University with a colleague, you know, well, Li Chun Luo, who's a world class neuroscientist. We've studied the complexity of the neuroanatomy of the dopamine system and these dopamine neurons in the ventral tegmental area, the source of the reward circuitry, dopamine, are receiving inputs from all over the brain. They're receiving indirectly or directly inputs from visual areas, from somatosensory areas. And I'm not giving you a really good answer because that's one of the goals of my research, to try to understand how, context, how the history that you've had with these cues, which we're going to get back to, of the donut or of a drug, how has that modified how this neuromodulatory system responds. Similarly, the nucleus accumbens, the target of this powerful modulator, dopamine, is receiving communications, what we call inputs from all sorts of brain regions that you know about, Andrew, your audience may not. It receives inputs from an area called the hippocampus, which you may have covered in previous podcasts, which is very powerfully, very important for memories, both establishing new memories and again, remember, that makes sense. You want this system, this dopamine reward circuitry to be very connected to memory systems. So the nucleus accumbens, the activity in the nucleus accumbens is modulated by dopamine, while it is receiving information from the hippocampus, which helps encode new memories, while it's receiving information from a brain area called the amygdala, which tells is a part of the brain involved in our emotional experiences. The accumbens also receives inputs from the prefrontal cortex, which is this brain area, as you know better than me, Andrew, is important for decision making, for planning our activity. And I could go on and on.

Well, could we talk about prefrontal cortex for a moment? Because it always was surprising to me that prefrontal cortex is talked about as this higher executive function area. But then when you look at the neuroanatomy, it's, as we say, monosynaptically, as you and I know, one connection away from structures like the amygdala, one connection away from structures like the nucleus accumbens. In other words, prefrontal cortex, to me, is every bit as ancient as some of these other structures that we think of as more ancient. And really, the whole ancient evolved thing gets a little bit dicey because certain areas like the prefrontal cortex are more elaborated in humans. But to me, the prefrontal cortex seems to be especially important in the context of this thing of scaling the reward response or context of the reward response, because it can set rules. It seems to know, okay, we're recording a podcast now, and there are certain rules. There are certain things that we're going to do and not do. But what's fascinating about the. And I'm so glad you gave a bunch of different examples, because what's fascinating, for instance, about the relationship example, is that, yes, at one moment we can adore somebody, and another moment later, if they do something or don't do something, we can be incredibly frustrated with them. They can even become aversive to us. Hopefully that doesn't happen too frequently. But I think we've all had the experience of a donut, an event, or a person actually looking different to us from one moment to the next. Hopefully not at random, right? And so to me, it seems like the prefrontal cortex is uniquely positioned to really say, okay, right now we are in a mode of, for lack of a better word, love. And loving, like be in the. In the verb tense of loving, be in the verb tense of arguing. We're now arguing, you know, we're in the verb tense of. Of. Of reconciliation, you know, kind of somewhere in between or something of that sort. And how a structure in a circuit as simple as the dopamine system, right? One molecule could suddenly say, oh, you know what? Now getting over my anger is rewarding, Whereas five minutes ago, being right and being the most angry was rewarding. And then five minutes before that, again, we're accelerating this movie. But five minutes or five days or five years before that, this Person could do no wrong. And the dopamine system is just cranking out dopamine, saying, whatever you do. I'm just delighted by it. Incredible. Like, to me, I can't think of a more interesting system in neuroscience.

Well, I mean, that was eloquently put. I agree with pretty much everything you said. I don't have much to add because what you're pointing out is the challenges of studying these systems, the importance of studying these systems, and the challenge of presenting how the brain works to this podcast audience. Because on the one hand, you have done a fantastic job over the last few years in your podcast of making complex subjects accessible to a lay audience. Thank you. And get them to be thinking about how our modern view of how the brain works could be used to enhance health, could enhance mental well being. But as neuroscientists, academic neuroscientists ourselves, we know, you know, you are oversimplifying things. And the actual functioning of a system like the dopamine reward circuitry, as you just eloquently point out, is so much more complex. It's modified by these prefrontal inputs which are simultaneously telling our memory systems, you know, pay attention here. I'm repeating what you just said. The context makes a big difference. The history you have with the person or stimuli with whom you're interacting. Like, to bring this back to your, you know, which I never. The initial question is a small piece of a donut activate the cue that that small piece of a donut activate the reward circuitry and cause release of dopamine to the same extent as the full donut. Depends on your experience with donuts. I mean, I think for you and me, because we seem to both like donuts, they're highly appetitive for us, probably doesn't matter, because we have learned even a little piece of a donut activates all of our memory system, saying, man, that's an old fashioned glazed donut. I want to eat that, I want to get one or I want to have the discipline not to eat it. So I hope I'm answering your question and I'm shifting topics completely, but that's why addiction is so challenging.

Well, let's talk about that. Let's talk about that because you've done a ton of important work in this area of addiction. I mean, one of the basic questions I have about addiction is we hear that certain drugs are more addicting than other drugs or certain behaviors. We also hear that we can become addicted to anything. When Anna Lemke was on this podcast, I said, what's the most unusual addiction you've ever seen? And she talked about a patient who sadly committed suicide at some point later that she told us had been addicted to water, to drinking of any kind. First alcohol, but then water eventually. And so my question about addiction in the dopamine system is, you know, let's pick a drug like cocaine. I've never done cocaine, but people who have done cocaine tell me that it feels very good. And one of the more salient features of the cocaine high is that it comes on very fast, and it ends pretty quickly, too. Is the rate of dopamine increase related to the addictive property of a drug or behavior as much as how much dopamine is released?

And that's a very sophisticated question. And the answer is yes. And that's usually the lecture I give the way I think about addiction. And obviously, my friend and colleague Anna Lembke is one of the world's experts in terms of the understanding the human experience of addiction. I have studied it as a cellular molecular neuroscientists trying to understand how addictive substances modify reward circuitry, modify the connections in the reward circuitry, modify how dopamine neurons act. And the way I, you know, like any what appears to be a simple term, it's layered with complexity. Addiction is somewhat of a continuum. And I like to think about whether you're talking about substances like cocaine, and I will explicitly answer your question soon, or opioids, as, you know, we're going, in this country, there is an opioid epidemic. I do like to think about addictive liability. And it is, in my view, it is pretty clear that when we're talking about drugs, they have different degrees of addictive liability. I mean, I had a cup of coffee this morning, and many of us listening to this podcast, it's really hard to start our day without getting that hit of caffeine. But are we addicted to caffeine? That's a tricky question, because I've never heard of anybody robbing a bank to get caffeine, destroying their personal life to get caffeine. So I would say caffeine causes tolerance, but I would not say it has a particularly high addictive liability. Whereas drugs like psychosimulants, like cocaine have a very. Or opioids have a very high addictive liability. So to answer your mechanistic question, there have been some famous studies done by the director of the National Institute on Drug Abuse, Nora Volkov. Simultaneously, there have been studies in animal models of addiction where you nailed it in a rough Way the addictive liability of a substance is directly correlated with two aspects of dopamine. How much dopamine is released in the incumbents and the kinetics of the dopamine release, as you said, how rapidly it's released. To get a little technical, even with a drug like cocaine or opioids, it's not only the drug itself, it's the route of administration. Because the route of administration influences the kinetics, meaning how fast that drugs gets into your brain influences the reward circuitry and how fast it causes a big rapid release of dopamine. And some of your podcast listeners may be old enough to remember the crack cocaine epidemic or freebase cocaine. And cocaine does have, like methamphetamine, a very high addictive liability. I teach the neurobiology. I give lectures to students at Stanford about neurobiology of addiction as part of a team course, team taught course. I have kids who I had to deal with. And what, you know, what I always say is, you know, you, it's not that if you use this drug, you're automatically going to become an addict, but you're taking that risk. And it is impossible to become addicted to a substance if you've never used it by definition. But back to the root of administration. So I went off.

That's actually an interesting statement, you know, because I think we may have heard that in high school. Although I, to be honest, wasn't the most attentive high school student. And I regret that high school students pay attention.

You did okay for yourself.

Eventually I came around, but there was an uphill battle there. But that you can't become addicted to something that you've never done. Which I just want to earmark that because I think it's a profound statement because it points to the importance of the memory system, but also plasticity. And so I want to make sure that eventually we get around to talking about how the amount of dopamine released and the kinetics, how that might influence plasticity. Basically, what I'm asking here, queuing up in the back of your mind, is whether or not addiction is just related to the sensation that we have when we indulge in a behavior or when we are under the influence of a drug, or whether or not it actually modifies neural circuitry in a way that makes a broader range of drugs or experiences attractive to us.

It's probably the latter, but so let me get back, and I will answer that in a second to the point I was making. So it's not only the substance, it's the root of administration. So, and, you know, as I said, you can't develop a problem with a substance and develop a substance abuse problem if you never take it. But snorting cocaine is a different experience than smoking it or injecting it. And one of the reasons the crack cocaine epidemic was so powerful is it gets into when you're smoking it or injecting it, it gets in. And people do this now with methamphetamine. I mean, meth addicts, most of them, and that is another epidemic in our country. Most of them smoke it. And that the danger of that is the drug, whether it's cocaine, methamphetamine gets into your brain almost instantaneously, causes a very rapid, powerful surge of dopamine in the accumbens in this reward circuitry. And that the feeling you get, which and we're going to get into this, is not necessarily a happy feeling. And it only lasts. It can last for tens of seconds or a few minutes. And it's a feeling that gives you this overwhelming compulsion and urge, I want to do it again. So even though it may not actually feel all that good. And again, this gets into, you know, we didn't have an addiction problem for any substance other than alcohol, you know, for most of humanity's existence, because these substances like cocaine, methamphetamine, synthetic opioids like fentanyl, they didn't exist. And our brain, you know, the truth is our brains are not designed to handle those kinds of very powerful substances.

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Want to go from here? You asked a question about, you know, the neural mechanisms of what we call addiction.

Yeah, I'd like to know about the role of neuroplasticity in addiction. I do want to highlight something you said, and I apologize for interrupting a moment ago. And then I referred, but it was an interruption based on real excitement because a. A person I know quite well who is a recovered cocaine addict told me, and by the way, folks, this isn't. I have a friend and I'm actually, you know, I truly have never tried cocaine. And this person said that the first time they did cocaine, his thought was, I hate this and I can't wait to do it again. And that's exactly how you described it.

And I think that is a fairly common experience with people suffering from an addiction disorder. We're not supposed to use the word addicts anymore because that's a little bit judgmental.

That's the new nomenclature.

Something along those lines.

Got it. Calling someone an addict as opposed to being addicted.

Yeah, being. And that is a beautiful description. I hate it, but I want to do it again and again. It just shows the power of this system which, remember, evolved for our survival. So a very simple way of thinking about it is these drugs are tricking the reward circuitry to say this stimulus, this experience is really important for my survival. I have to go do it again and again and again. A side question is the huge question is why do some people develop an addiction problem and others who have used this substance just don't? And again, as a world class neuroscientist yourself, you know the answer. It's always a complex combination of underlying genetics, the environment in which they find themselves, the environment in which they grew up, and how that modified their reward circuitry. So to get at your question, one set of experiments my lab did, which other labs did too, I don't deserve the sole credit for this. Is showing that drugs of abuse cause powerful plasticity in the neurons that make up the cells that make up the reward circuitry. And in fact, drugs of abuse like cocaine, methamphetamine, opioids, like morphine, heroin, change the synapses. The synapses are the connections from other nerve cells onto dopamine neurons, onto the nerve cells and the accumbens. And these connections, these synapses can change. And drugs of abuse cause powerful changes in those connections and therefore powerful changes in the activity of the dopamine neurons. And the neurons in the ventral, in the nucleus accumbens. In fact, the types of changes that occur appear to be similar to the types of changes that have evolved for good uses for adaptive forms of learning and memory? Again, this is an example that this, a superficially simple dopamine reward circuitry, is changing all the time. It is highly plastic and can become more sensitive to certain experiences, you know, et cetera, et cetera.

Well, could I ask a question about some of the general contours of the plasticity and the dopamine system? You said before, and I love this statement, even though it's very simple, but in its simplicity, it's really elegant, that we can't become addicted to a substance or a behavior that we haven't taken or partaken in. So is there data to support the idea that just one exposure to cocaine or one exposure to some sort of behavior can lead to a lasting change in the dopamine system such that one's propensity to be addicted to that substance again, if one were to indulge in the future or behavior again in the future is increased? And I have a very particular reason for asking this, but I'm very curious what the answer is.

I mean, in the work my lab and other labs have done in preclinical rodent models, the answer is yes. A single administration of a drug of abuse, like cocaine, like morphine, can cause relatively several days, several weeks of changes in the connections onto dopamine neurons and onto the neurons in the nucleus accumbens, those changes. That does not mean these changes are permanent or irreversible. But the changes last a long time. And again, the big question for understanding the neurobiology of addiction is, you know, those changes are probably happening in most people who take the drug in this case. And we can talk about other stimuli, non drug stimuli that can become, in quotes, addictive, you know. Again, why in certain individuals, to be honest, it's not a big deal. Yeah, I did cocaine at this party. It was nice, but I don't feel any craving or urge to do it again. Whereas other individuals, it sets them down a very bad path and really badly affects their life. And that's a huge question in the research field because obviously, if we could make predictions on which individuals are more susceptible, and not to get too political here, but it's also, whether you develop a problem with addiction or not is influenced by the other parts of your life, do you have other ways of getting reinforcing stimuli, getting satisfaction, having an outlet that other ways of activating Your reward or dopamine circuitry. Healthy, you know, healthy ways.

Right.

Like, you know, as you have articulated, I think, in. In your podcast, getting exercise. You know, you and I both like to get exercise. I feel really good. Sometimes it's painful during the exercise, but afterwards I feel great.

Very. Almost the inverse of the cocaine response.

Yeah.

The desire and then the. I hate this, but I can't wait to do it again. It seems like exercise is often the opposite, because I hate this. I. I don't want to do this. And then afterwards, gosh, I always feel better. And I'd be happy to do it again.

I mean, yes. I mean, I like to exercise chasing a ball, because that gets me off thinking about this hurts. But so, anyhow, back to addiction. So, yes, these drugs can cause. I don't want to. Definitely not permanent changes from a single exposure. You know, and the types of studies I'm talking about were all done in, you know, experimental animals. So how that relates to what happens in our brains and human subjects brains is not completely clear. But I think there are parallels. So the changes might last, you know, a few days, a week or two. But one can see if somebody. There have been studies done where in an animal model, if you give repeated administration of a drug like cocaine, the changes get stronger and they last longer, which is kind of intuitively obvious. But again, the big question is why in human subjects, there are people who can use these substances and not develop a serious problem, and there are others where they're. They're very, very damaging. And, you know, and then that's why I still make the point. If you're a young person, if you're. Do you want to take that risk? Is it worth it to have that experience? And that's an individual decision.

We've done some podcast episodes about alcohol, cannabis, et cetera. And there does seem to be a pretty wide variation in people's response to the information, I think, because there are people out there who. Well, I've got friends who are recovered alcoholics who will tell me the first drink they took. They used language like it combined with the chemistry of my body in a way that nothing before ever had. And they felt like it was like this magic elixir. That has not been my experience.

And I have heard the same stories. And it's hard for me to relate because, like you, alcohol does not have that effect on me. And that's where it's hard to believe that kind of immediate response to alcohol is due to the environments in which they grew up. Although that can have an influence that just feels almost more genetically encoded. And there is evidence that issues with the use of alcohol and developing alcohol use disorder does run in families. And obviously, if it runs in family, you have to worry about how the environment of that family influences it. But there's a lot of studies saying there is a genetic component. Maybe like you, if I have a drink or two in the afternoon, I just fall asleep, and it does not have that effect on me. And one could imagine similar things for other drugs of abuse. There are people who have used cocaine, have used methamphetamine, who, you know, who find it modestly enjoyable. But it's not, you know, the be all or end all. It isn't this incredibly powerful experience. And you just talked about, I think, a friend or a colleague who said, I hate it, I hate that, but I want to do it again. And that's fascinating.

Yeah, they're now a recovered alcoholic and cocaine addict, and they've abstained for many years, but still get a little bit of a gleam in their eye when they talk about alcohol or cocaine in a way that I just can't relate to.

I can relate. I mean, can I tell you a little vignette about me, which I love to tell. And it gets into how the reward circuitry is so closely associated with memory systems and how cues associated with powerful experiences develop their own reinforcing or aversive quality. So, long story short, when I was a young kid in, I can't remember, in my 20s, maybe 20, I spent a few weeks in Paris. I started smoking cigarettes. I mean, this is a long time ago. And I got. Cigarettes are very interesting. Nicotine is highly addictive, as the tobacco companies were fully aware of.

High addictive liability.

Very high addictive liability.

People will rob people for the money to buy cigarettes.

They may not rob because although my understanding is they've become quite expensive. But I guess the vote significantly, counterfeit cigarettes are a huge market for organized crime. There are parts in the world, third world countries where organized crime produce counterfeit cigarettes and are making hundreds of millions or billions of dollars. And so I think nicotine as it is delivered in cigarettes, as you know, I mean, tobacco companies put in a lot of work to figure out the exact dose of nicotine that will make you get that kind of feeling that only lasts for a few minutes. So you want to do it again and again so we can talk about the. And nicotine, you know, what becomes a problem in a specific society with addiction is not only based on the neurobiological Actions. If we're talking still about drugs or substances of that substance, it's heavily influenced by the availability of the substance. But my little story is I smoked some cigarettes in Paris. I learned why people like to smoke. It was very satisfying to have a cigarette in a Parisian cafe. It just, you know, and it's very interesting because the first few times you inhale tobacco, you get dizzy. It's kind of aversive, and it's exactly what you articulated. Despite that, you want to do it again. So it was just a lot of fun for me. I enjoyed it, and I was disciplined. You know, at some point, whenever this was. I came back to the United States, I didn't smoke because I knew it was bad for you. But to this day, 40 years later, every time I go back to Paris, I get cravings. I actually just want to get a pack of cigarettes. I want to have that feeling again of inhaling the smoke. But the point is of how powerful these rewarding experiences can be or reinforcing experiences. And for your audience, technically, what I have been taught by some of my psychology colleagues is we use the term reinforcing in a very behaviorally defined way. Something is reinforcing is the behavior that led to that stimuli. It makes you want to do that behavior again. Rewarding means that it actually felt in quotes. Good.

That's an important distinction.

Actually can be different again, as you defined by your friend, who his. I forget. I think it was cocaine. Cocaine was highly reinforcing, but it was not necessarily enjoyable or rewarding. And isn't that fascinating? I have some colleagues in the addiction field. One of them is retired now. Kent Berridge and Terry Robinson. They distinguish between the terms wanting and liking and think about that. Liking something means it's something you like. You enjoy. Wanting means you want it, but you don't necessarily like it or enjoy it. And that's a description of your friend's experience with cocaine. Some of us have been in destructive relationships where you want that individual, but you're not sure you necessarily like that.

And sometimes people will be in relationships where they actively dislike the other person, which is a bit foreign of a concept to me, but. Well, it's interesting, this separation of reinforcing and rewarding, wanting and liking. Because one of the things that's very prominent in 12 step programs is to create rewards around abstaining from the drug or behavior. And I should mention that programs like 12 Step, when followed, seem to have very high success rates. At least that's what Anna Lemke tells me. That in some ways they are modifying the wanting and liking. They're splitting the wanting and liking of, you know, alcohol, for instance, creating a liking of sobriety more than the wanting of alcohol, for instance.

That's beautifully put. And I think that's right. How that plays out in the neural mechanisms that as a neuroscientist, I'm interested in. Man, that's a tough one. But I think that's why those programs are pretty successful. It's helping the person make those dissociations. And I don't know that much about those programs because I have not seen patients myself for whatever it's been, 27, 28 years. But I think part of them are to help that individual find, as you, both, other sources of liking and reward. Getting some satisfaction and reward from the actual abstinence, being able to cognitively teach themselves that I deserve a pat on the back, I deserve credit. I feel good that I did not take a drink at that party, that I did not use that substance again. And how that plays out in our brains is a really tough one.

Yeah, those are the way you described it is exactly right. Those programs are highly reinforcing for abstinence behaviors. Everything from the social connection, which we're gonna get to social connection as you know, to the way that people start to conceptualize their addict self versus other self. It actually involves a splitting of the self in interesting ways. As long as we're talking about donuts, cigarettes, alcohol, cocaine. I'm curious, before we move to a bit more on neuroplasticity, is there anything that people ought to know about how different substances and behaviors that are addicting might impact the dopamine reward circuitry differently? So, for instance, we talked about cocaine as having this very rapid onset, big increase in dopamine, then a crash, as we know, a certain pattern of kinetics as you describe it. The opioid crisis is incredibly serious problem right now, as is methamphetamine. But it sounds like methamphetamine functions a bit like cocaine and in terms of its kinetics. So an opioid is a very different chemical than cocaine, but it sounds like it impacts the dopamine system. Is the dopaminergic activity caused by opioids responsible for the addictive properties of opioids, or do people also like the feeling of being under opioids? I personally hate it coming out of surgery. Like, they gave me Vicodin once and I hated it. I'd rather have the pain, the post operative pain, than take something like Vicodin. Or a valium or fentanyl or anything like that to me, is just completely aversive. But I realize that there are many millions of people that feel quite differently.

It's a great question. So I think all the studies, both in human beings and pre clinical animal models. Yes. Would suggest that the addictive liability of opioids and psychostimulants, which are cocaine and methamphetamine, have the common final action of causing massive release of dopamine in this target of the dopamine neurons, the nucleus accumbens. They do it, if we want to get a little scientifically technical here, via very different mechanisms. So cocaine and methamphetamine, the drugs known as psychostimulants, actually bind to a protein in the brain or a molecule in the brain that is responsible for sucking up. It's a vacuum cleaner sucking up the dopamine after it's been released. And cocaine prevents that dopamine from being vacuumed up, so the cocaine hangs around longer. Meth not only prevents the dopamine from being vacuumed up, it actually causes the reverse. It actually causes the direct release of dopamine from what we call nerve terminals from the site where dopamine's released. Opioids work very differently. They actually primarily not solely work where the dopamine neurons live. And it's a little complicated. It's not that critical, but they indirectly increase the activity within the dopamine neurons themselves, causing a big, massive, bigger than normal release of dopamine. So that's one commonality. But anybody who has used these drugs or read about these drugs, the subjective experience of the drugs are dramatically different, and that's because of the actions they're having, not only in the reward circuitry, but throughout the brain. So. And it's interesting, you talked about Vicodin. I've taken Vicodin because I've had several knee surgeries and things. Like you, I didn't like it. I've gotten other opioids for pain relief that were great. I mean, they took. They took away a lot of pain after my ligament repair. And that's a different question, that even when you're talking about opioids, all drugs are not. They're not identical. Fentanyl has a much big, larger addictive liability because of its molecular properties and how it's interacting with the opioid system in our brains and the receptors, the actual proteins in the brain that it interacts with. But the subjective experience of opioids, I mean, it's interesting. Some people love it that's, you know, if we go back in history, as you know, there were the opium dens throughout Asia there were wars about opioids, the famous opioid wars between China and the United Kingdom. I mean, showing you how powerful the availability of a substance like an opioid can be. So I'm going off on a tangent, I apologize, but commonality is dopamine release in the incumbens. But if you remember what a Venn diagram is, all these drugs have some common actions, usually on directly or indirectly causing the massive release of dopamine in the incumbents. But then they have their own individual action because obviously when you take cocaine or methamphetamine, it's a stimulator, people are grinding their teeth, they're hyped up. For most people, opioids are the exact opposite. I mean in opium dens, from the movies I watched and watching narcos and all those TV shows, you're often, you're lying down, you're kind of in almost a dreamlike state. So very different subjective experience experiences.

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So. Interesting. Have you ever taken cough syrup with dextromethorphan?

No. So I avoid that stuff.

Well, I, you know, I have, I have a tendency when I get a cold, it gets into my lungs, I cough a lot. And I think this has been reported. This is my anecdotal experience. I'm confirming what you said. Dextromethorphan is a different sort of opioid and actually some people develop a problem with it. For me it gives me really bizarre dreams. Really similar to what you were just saying.

It was very unusual.

And that's a whole different conversation about what makes us dream and what are the meaning of dreams. Fascinating. And I hope you covered. Maybe you've covered that.

We have not yet, but we are intending to do a whole series on sleep and dreaming.

That would be a. Definitely get into it. I started out in sleep research so I have a fondness for it.

Drug research and sleep research have a long history of overlap with Alan Hobson's work on lsd.

I worked with Alan Hobson. Okay.

By the way folks, if you're interested in the relationship between hallucinations and dreaming, Alan Hobson is a good name to start your. Your rabbit, rabbit hole.

19. Oh my God, I'm dating myself 19. Oh, 70. I can't remember if it was 76 or 77. I worked with Alan Hobson as an undergraduate.

Harvard Medical School.

No, as an undergraduate at Harvard. He was at Harvard Medical School. Yeah.

Amazing. I love his writing and I learned a lot from it. He was really ahead of his time.

Yes, he was.

We'll get.

I was. Nobody would. Anybody who knows me won't believe this, but I. Back then I was a very shy, insecure, you know, 20 year old would.

Not have guessed who.

Oh I. And even in medical school I, I literally was not confident of my opinions at all. I was very shy. Was thought all of the ideas I had must be Obvious. And I should never say them out loud.

Do you mind if I ask? Since you raised this, I think it's really important. I mean, you have this incredible career track record. You're adored by your colleagues, you're highly respected, you've won just about every award there is to winning neuroscience. So was there something in particular that. Was it an overnight thing where one day you woke up and thought, you know, I actually believe in myself. But if you wouldn't mind sharing that, because I think before we get back into some of the science, you know, this is. Science is a human endeavor and most people listening are probably not scientists. But I think everybody deals with these issues of self doubt and people appear to have varying levels of confidence. But what happened?

Thank you for asking. For me, it was a very gradual process. And I'm not, as an undergraduate, as a medical student, even as a postdoc, yeah, I was very unsure of my ideas, of my intellectual abilities, of whether what I was thinking was really, you know, worthwhile. So it was a very gradual process. I think it, the increase in my confidence, I think began when I was a postdoc, which is a training period after you've done received a PhD or an MD where you get additional research training. And I worked with a guy named Roger Nichol at ucsf. And Roger was a very intellectually intense, very forceful individual. And I got involved in a field where, I mean, people. A little bit of a tangent. Your listeners may think that scientists are these geeky individuals wearing white coats with no passion or emotion. And nothing could be further from the truth. The most successful scientists I know are pretty passionate and pretty intense about what they're working on and driven. I mean, and this is a gross generalization. So anyhow, during my postdoc I started getting involved in a topic where there were vigorous arguments about phenomenology we were studying. So I had to develop a tougher and thicker skin. I had to be able to argue my side of the hypotheses we were generating. So it started developing as a postdoc and then it slowly evolved as an assistant professor. And for your listeners who don't know, I don't like to admit this, but I'm in my late 60s, I have been running my own lab for almost 40 years. So gradually, as an assistant professor, I realized, hey, I can do this, I can do science, I can write papers that my colleagues seem to be interested in. And then gradually, over then the next 10, 20, 30 years, I, I gained more and more confidence. I. So for me, it Was this very gradual buildup of many different experiences where I developed some confidence that, you know, not all of my ideas are great. Of course they're not. But it's okay to voice my opinion. It's okay to state my ideas and why I believe this and why I don't believe that. So that was my experience.

Thank you for sharing that. Because I think, you know, people struggle with that very issue. And clearly showing up again and again over a long period of time is helpful. But as you said, you know, learning to trust one's ideas. Just a brief anecdote when I was coming up in neuroscience. A few years behind you, 20 years behind me. Not too many. I mean, two decades, but. But I recall the incredible number of high profile papers on neuroplasticity and long term potentiation. Long term depression. These are terms related to the modification of synapses that Rob Malenka and Roger Nicole pioneered a big segment to that work. And I remember seeing your names on papers and I thought Roger worked for you. Sorry, Roger.

I love to hear that.

I was under the impression for you and only later did I learn that you were his postdoc.

So. And then. And then we collaborated as equals.

You became peers very quickly.

Very quickly.

Yeah. So you've had a.

And Roger, you know, I. Roger's wonderful. I did have the confidence, even as a postdoc and actually even as a grad student. Even though I was a little insecure about my ideas, I wanted to be treated as an equal. That's the one thing I did have. I never felt that I was working for somebody else. I always felt that I was working for myself and that we were colleagues, even though my mentors had more experience and I could learn from them.

I like that you're working for yourself even though you have mentors. I think there's some real gems in what you just described. So thank you for taking the time to do that.

Sure.

I'd like to discuss one aspect of reward circuitry that I don't think most people think about. Fairly straightforward nowadays. I like to think more people know what dopamine is and understand it, thanks to your work and Ana's work and some discussions that have taken place on our podcast, other podcasts. But, you know, all too often we think dopamine reward wanting, liking drugs. Okay, all of that is great, but what about the truly adaptive stuff? Right? Because it's easy to fall into a discussion around dopamine of, you know, the things that are bad for us. But what I'm thinking about here Is social interaction. Yeah, clearly we are a social species. And a lot of your work in the last decade and a half or so has focused on the relationship between the reward circuitry, which you beautifully described for us, and social interaction and connection. And where I'm going with this is ultimately, this has huge implications for autism and autism spectrum disorders. I don't know if nowadays, is it okay, you're not supposed to call autism a disease, Is that right? You hear about neurotypical and neuro atypical, but is. But I have friends who have children who are severely autistic, and I don't know many parents who would elect to have a severely autistic kid. And so those people often will talk about it as autism or a child having autism. So first of all, before we get into the social piece, maybe because I just tabled it, what, how are we supposed to talk about autism nowadays?

I am very interested in the pathophysiology of what the medical profession terms autism spectrum disorder. As you pointed out, the individuals living with an autism spectrum disorder are quite heterogeneous. And it can range from individuals with severe intellectual impairment and quite severe impairments in social interactions, impairments in sensory processing impairments, and lots of different aspects of our behaviors that are important. And I think nobody would say, would argue those individuals on the severe spectrum do not have some sort of in quotes disorder. The issue we have to be sensitive to is it's a heterogeneous disorder. Like many brain issues that psychiatrists deal with, like depression, we all like obsessive compulsive disorder, like various anxiety disorders. It's always on a continuum and a spectrum. So for autism spectrum disorder, there are individuals who are high functioning, who one could argue, have a different style of interacting socially, may have a different way of processing sensory information, but who would prefer not to be viewed as having an illness, but rather would be viewed as having a different style of living and interaction. And I think we need to respect that. So the challenge is, again, not oversimplifying a complex heterogeneous disorder and both being respectful of the people who don't want to be defined as having a neuropsychiatric or brain disorder, while equally being respectful of people like your friends with severely impaired children who deserve help, who deserve research. And it's a tough one because my understanding from, to be honest, just reading articles in the lay press and going to websites from organizations that philanthropically support research related to autism within that community of individuals who are not researchers, but who have family members or are themselves Dealing with some degree of autism spectrum disorder. There's disagreements about how to, what terminology to use, how to deal with them and it's complicated. I think we just have to respect everybody. And if you're interacting with individuals, you know, I think it's appropriate. What do you prefer? I do know as a medical professional and especially when you're dealing with children, there are children who need help and we're not doing them a service by saying they don't have an issue that we should be helping them with and working on. So I hope that answers your question beautifully.

I think it beautifully answers it and encompasses all sides so that we can move forward. And I think we'll. So as we use the term autism or children or people with autism, that's what we're referring to.

I think people are very sensitive, especially those individuals who are neuro atypical who previously might be diagnosed as autism spectrum disorder but would prefer to not be labeled as having a brain illness. That's fine. It's kind of. Once you are an adult you can make that decision for yourself.

We certainly have colleagues at Stanford and elsewhere who, at least by my non clinical assessment, seem to fall somewhere on that spectrum.

And again, it's a continuum, just like, you know, the experience of depression is in a continuum.

But all right, as with depression, you wouldn't love a child or an adult any less because they have depression. Nor would you love a child or adult any less because of expression of some autism.

I know the point people don't, you know, and so we are being trained in the medical profession to be very, in our society is going this way too. Very careful with the terms we use and the labeling of individuals. So you know, I've been taught you can say individuals living with an autism spectrum disorder. Some people don't like using a term, oh, that individual is autistic because that has some can have some, I don't want to say derogatory meaning, but some labeling kind of. But you know, sometimes this gets out of control too, as we both know.

Well, for sake of fluid conversation, we will do our best, but we will acknowledge from the outset that we are well meaning but far from perfect in how we'll handle this.

Well put, well put.

So in thinking about social interactions and leaving aside anything related to autism for the moment, it appears that the circuits in the brain that mediate the desire to spend time with others of the same species, maybe even with other species, like a dog, are fairly hardwired but modifiable. We were born with the capacity to build them up and that social behavior is highly rewarded. Is it rewarded through the dopamine system? And what, if any, involvement is there of the serotonergic system? And we haven't talked about serotonin yet, but I'd love to bring up serotonin at this point. Maybe you could educate us a little bit about serotonin because, gosh, if dopamine is fascinating, serotonin is at least as incredible.

Yeah, great question. So I think for me, the easiest way for me to answer it is actually just tell you my research history and how a lab like mine at Stanford that at one point was studying what I, what you and I would call fairly hardcore molecular mechanisms of neuroplasticity. How do connections between nerve cells change and what molecules are changing and pretty hardcore molecular stuff. How did I end up studying social behaviors in mice? And what I hope we'll end up talking about, even developing behavioral models of what I will define as empathy in mice. The answer is very simple. My lab was working on roles of classic dopamine reward circuitry and how it changes in models of addiction. We haven't talked about depression models of depression because just intuitively, hopefully your listeners can understand if one component of depression is what we call anhedonia, the inability to experience reward. You know, eating a donut is no longer satisfying. Having sex is no longer that much fun, which is a component of depression. If there's a mechanism in the brain that tells you something is rewarding by definition, that's not functioning normally in severe depression. So we were doing models of depression to figure out how the dopamine reward circuitry was changing, as were many other labs we were studying addiction. Those were the obvious ones. And I mean, it might be entertaining to your audience to learn how academic scientists think. I was thinking those are fascinating topics. They're pretty competitive. Lots of other labs were working on it and I started thinking what other experiences might be modifying the reward circuitry. I actually made some attempts to look at feeding behavior, but I don't want to. I mean, we actually never pursued that for a variety of reasons. And that's obviously important because of there is an obesity epidemic in this country and we can talk about how the reward circuitry and some of the things we've learned from our studies of addiction may be helpful to understanding obesity. But back to social interaction, I started thinking, well, for most of us, what I call a pro social non sexual experience is highly reinforcing. Andrew, you're a pretty social guy. I'm a pretty social guy. Most of the time I'd rather go to a movie, a sporting event, a dinner with friends. It's actually for me, the most meaningful component of my life, other than spending time with my children, is spending time with my close friends. And I started thinking, well, why is that? Why do I have such a good time going to a ball game with my best friend or going out to dinner with another couple and interacting? It's because, well, it's highly reinforcing. And if it's highly reinforcing, it must involve the reward circuitry. And then I started thinking, evolutionarily, it makes a lot of sense because if you are part of a social species, there's a lot of evolutionarily, a lot of advantages for your survival to be hanging out with other members of your species in a non aggressive way. It can increase your likelihood to find a mate and reproduce. It can protect you from predators. I mean, that's why any of your listeners who ever watch wildlife shows or National Geographic shows, there's a reason all these animals hang out together, it's for protection from predators. So there are all these reasons. So about whenever it was 13 or 14 years ago, my lab decided to start looking at how the reward circuitry may play a role in what I am going to call positive pro social, non aggressive interactions. Another word we use is just sociability. And for a variety of reasons back then, this is at least 13 years ago, maybe 15 years ago, a postdoc joined my lab named Gul Dolan. She's now a professor at Johns Hopkins and she had an interest in oxytocin. And as your listeners know, oxytocin is this evolutionarily conserved neuropeptide that's very important for parturition, having a baby born for milk being produced. And it's gotten a lot of attention as a potential love neuropeptide, as something that is released in our brains during a positive social interaction. There's a well known researcher in social behavior and bonding research called Larry Young and he did some very important, now somewhat classic work studying a species called the vole, in particular the prairie vole. And prairie voles are a species where they mate for life. It's called pair bonding. So one vole will find another vole, they basically get married, they have kids and they hang out together for the rest of their life. No divorce, no 50% divorce rate, no 50% divorce rate. And what Larry elegantly showed in part in early days, in collaboration with a guy named Tom Insull, who is a famous academic Psychiatrist, they showed that oxytocin action within the nucleus accumbens, within this reward circuitry was required and really important for this monogamous pair bonding. Having said that, there was just a paper that called into question that. But that's.

But there's 30 years of research prior to that. I'm glad you brought that up because we'll keep this contemporary. And the reality is that that recent paper got a lot of attention.

You know the paper I'm talking about. Yeah.

That maybe oxytocin isn't playing as prominent a role in pair bonding as people had thought. And yet, folks, that could be true. We have to be scientific about this and be open minded. But there's, you know, three decades of work that, that speaks to the contrary. So I think we want to be a. We want to weigh the evidence.

Yeah, exactly. And again, the, the investigators who presented the work saying oxytocin may not be as important, there are limitations to the manipulations they did, which they would agree with. So I'm just telling you. So Gouldolin was a postdoc in my lab and we decided, we formulated a project to look at the actions of oxytocin in the nucleus accumbens in mice. And the reason we study mice is they're what are known as a genetically tractable organism. We have all sorts of really cool and sophisticated tricks we can do to probe brain circuitry, the actions of neuromodulators like dopamine and serotonin and oxytocin in ways that we can't do in other species. And I'm going to get back to dopamine in a second. And what we found was that oxytocin action in the nucleus accumbens was indeed important for promoting sociability, probably for promoting the reinforcing component of a social interaction. And that surprised us. You know, it was like, wow, it's. Oxytocin seems to be causing, enhancing the release of serotonin in the nucleus accumbens, and that perhaps we'll get to this. That led me off on a whole series of experiments trying to figure out how serotonin works, studying this drug we may talk about called mdma, which is ecstasy or Molly, which actually causes release of serotonin. So we did that work and that got us working in serotonin simultaneously. There were some other papers reporting that dopamine release in the incumbents, that dopamine is released in the incumbens during a social interaction, a positive, non aggressive social interaction. Truth be told, it may also be released during an aggressive interaction. Some people like to fight, some people like to fight. And the difference here is the dopamine release and its role in social interactions. It's not specific only for social interaction, as we have talked about, but nevertheless, that led my lab and other labs to do a series of papers. I'm talking about the field now showing that, and I'm giving you a lot of information here. So how might dopamine release happen during a non aggressive social interaction? It turns out that oxytocin is not only released in the nucleus accumbens, it's released in the home of the dopamine neurons in the vta. So my lab and another lab from Northwestern showed that oxytocin can actually modulate dopamine neuron activity in the ventral tegmental area. So I hope I'm making sense here. I don't want to get too technical, but it just shows how we discuss these neuromodulators like dopamine. I just brought in oxytocin. We're going to talk about serotonin in a second. Unfortunately for your listeners, they don't work in isolation. They influence each other in ways that I think it's important for us to understand and elucidate.

That is not too much technical detail. And I think it's wonderfully rich with areas for us to discuss. And I'm so very glad that you brought up that neither dopamine nor serotonin nor oxytocin work in isolation, because all too often, and admittedly, sometimes even on my podcast, I'll talk about these things in isolation as a way to try and simplify them a bit. But. But there's just no way that the brain works that way. You know, for instance, turning on dopamine and turning off serotonin, it's a weighting of inputs. And I think that serotonin, perhaps I should frame it this way just as often as dopamine is framed as this reward molecule and pleasure. And dopamine hits all too often. I think in the popular press, serotonin is discussed, and oxytocin too, for that matter, as this kind of warm feel good, everything's mellow, you know, not really associated with reward and reinforcement. And of course, it's not that simple. So when it comes to social interactions, it sounds like oxytocin and serotonin are playing a prominent role also in the accumbens and that dopamine is. Is activated too. Do I have that right? Okay, so I don't want to take us Too far down the rabbit hole of neural circuit function. But that, to me, makes at least a brief discussion about the nucleus accumbens itself. Interesting. Like, okay, so I'm thinking nucleus. I know that means a pile of neurons, an aggregation of neurons. It's talking to this ventral striatum. So we got a bunch of neurons.

Part of the ventral striatum, part of the vent subdivision.

Excuse me, I misspoke. Yeah, it's part of the ventral striatum, and it's. And the neurons there can be active and communicate with other brain areas, but we're talking about a lot of nuance of function.

Oh, man. So I'm not smiling. I don't know if your audiences can see me smiling because it's so. I sometimes go to bed feeling it's so complicated. Oh, my God, it is.

And yet, could we say that within the nucleus accumbens there are neurons that are acting as accelerators and brakes? I mean, is there a simple analogy that perhaps, while not exhaustive, can still be true? Because that's always the goal on this podcast. There's no way we can be exhaustive, but we want to be as accurate as possible.

So a very influential hypothesis which has guided my thinking. And again, the trick. I mean, you know, you have done a wonderful job of communicating complex scientific topics to your podcast audience, and I congratulate you on that. And it's really. It's a really important role. But as you know, it's always more complicated than we want it to be as scientists, especially when you're dealing with brain activity issues and how the brain mediates all its amazing functions. So, historically, we have thought about the nucleus accumbens and other components of this ventral striatal brain area as primarily being composed of two different cell types, and as you pointed out, one being sort of an accelerator, something that promotes certain behaviors, and the other cell type somewhat being a break saying, don't do that behavior. Don't perform that motor action. And it is true that there are these different cell types. It is true that they are modulated by these modulators like dopamine and serotonin in different ways. And that simplistic hypothesis, or heuristic we call it, has been very useful in making models about how the accumbens does all its wonderful things. What I'm leading up to is, unfortunately, it's a little more complicated. But, yes, there are two different cell types, and at least for your audience, we can think about dopamine driving the activity of one, promoting certain behaviors and inhibiting the Activity of the other cell type and being a sort of brake on certain behaviors. As long as you and I, as scientists appreciate it's not quite that simple, It's a little more complicated.

So using that as a framework to think about social behavior, as you said, pro social, non aggressive, non sexual interactions involve the choice of a lot of behaviors, but also the suppression of a lot of behaviors. And so maybe you're starting to sense what I'm doing here. I think for people to understand how a single structure like the accumbens could mediate social interaction and reward it, what it sounds like it's doing is rewarding a certain category and catalog of behavioral options and punishing or at least reducing the probability of the occurrence of other behavioral actions. Because when I go to dinner with friends, if I know them really well, I might hug them, I might even say something mildly inappropriate if I know the context to be safe. Right. But at a dinner interview or a discussion with somebody you know, I barely know, I might watch my words a little bit more. Yep.

For instance, and I think the incumbents and its associated circuit. I love the way you just put that probabilities. It's my probability of having this behavior in a certain context is increased. My pro. The probabilities of not doing certain behaviors. And I think there's little doubt that this brain area called the nucleus accumbens and all of its associated circuitry play a very important role in what behaviors you choose to do pursue. Play a very important role in these making the decision and performing these pro social, non aggressive, non sexual interactions. I actually also think it plays a role in empathy and I'm leading you there. I want to have a discussion about that, please. Again, as a mechanistically driven neuroscientist, what is frustrating for me is I know a lot of the connections it's making and the other brain areas it's communicating with. But I can't give you a coherent hypothesis or diagram of how it all happens yet.

You're still going.

What I can say, say is even at our current level of understanding, it is leading to novel hypotheses that are allowing the develop, you know, perhaps, you know, if we bring it back to autism that are allowing the development of novel at the, at the moment, pharmacologic therapeutics that might be helpful for people who are not having normal pro social interactions and would like to have them, would like to be able to function in that domain in a more adaptive and productive and meaningful way. And that's the importance in my view of the kind of mechanistic work my lab and many other labs around the country are doing. Even if we don't have a detailed understanding of how it's all happening, we can identify drugs and druggable targets or even behavioral interventions that might actually help people, for example, suffering from autism spectrum disorder of the sort that they actually want and need, interact, need therapeutic help.

I think looking at the social connection circuitry through the lens of autism is going to be very interesting for us to do. I do have a question about what is being selected for in rewarding social interactions, because obviously we are living in a time where, you know, we don't have to aggregate in groups necessarily to protect ourselves physically. It helps in certain ways in certain circumstances, but certainly to support ourselves and each other emotionally. You know, having people that we can call on when we're not feeling so well, that we can look to for resources and that they can look to us. But when we go out to dinner with friends, or we go to a ball game with friends, or we interact with friends, I'm very familiar with the feeling of like, wow, that felt really good. It just felt good. It gives me energy. It actually gives me energy to go back and do other things like spend four days alone with a bunch of papers and lectures, preparing for a podcast, which I also really enjoy. But when I do that, when I go out to dinner with friends or see friends, I'm not thinking about buffering myself against loneliness when I do it. I just like the interaction. So what sorts of evolutionary hypotheses can we come up with as to why the human brain is so tuned for these social interactions, why it's rewarded by not just one dopamine, but also serotonin. Serotonin and oxytocin, three prominent neuromodulatory chemicals in the brain, are devoted at one site in the brain and others that it's connected to, of course, but to making sure that we do this as often as possible without giving up the rest of our lives.

Well, I mean, again, I think the answer I'm going to be able to give, I hope it's not trite and it may be a little bit obvious, is. And in some ways it's analogous to why drugs of abuse and addiction are also a problem, is that the circuitry that is telling us a pro social positive interaction is so highly reinforcing, evolved over millions of years or hundreds of thousands of years, whatever that is. And I. The only hypothesis I can come up with, and Andrew, you may be able to come up with Better ones is what I alluded to earlier is that it was very adaptive when we were more primitive organisms, nevermind non human primates, but when we were whatever we were to be a social species for basically primarily two reasons. For reproductive purposes. It increased your likelihood of reproducing if you were hanging out with other members of your species in a non aggressive way and for protection against predators. And there may be other reasons, probably child rearing. Oh yeah, thank you.

In your absence, you want trusted friends that can watch your offspring.

Thank you. Very good point. So the circuits, the modulators we use, that evolved over millennia and as you pointed out, you know, eventually, I mean, depending on the society in which you live, you didn't need those social interactions for protection against predators. Although, you know, if we look at our world now, one can make arguments both ways. If you're in a war zone, is it better to be off by yourself? Is it better to be with a group of people? But. So the mechanisms evolved for one purpose and they don't just disappear because there's no disadvantage to having this mechanism that tells us a social interaction is reinforcing. And I would still argue there's benefit for reproductive purposes. You can't have kids if you're by yourself all the time.

Well, and this is actually, I think.

It'S impossible, at least currently. And you can't find a partner with whom to have kids if you're socially isolated or it makes it much harder. So I hope I'm answering your question. I think. And then, and then, as you pointed out, you know, for many of us there's a lot of positive aspects to having friendships and hanging out with your friends. Emotional support, emotional buffering and feeling connected.

There's something connected. This notion of feeling connected, I'm. And later we'll talk about psychedelics, but this notion of feeling connected has a lot to do with buffering loneliness when we are alone. The memories and the energy, for lack of a better word, that we feel in recalling social experiences and anticipating social experiences is really powerful. You mentioned that people can't have children if they spend all their time alone. It's actually, I realize you're not on social media and more power to you, but this is actually a prominent discussion on social media. There's an entire culture of young people, in particular young men these days, who, at least from what I understand in the research literature about this, are socially isolated, spending all their time online, maybe not even on social media, but are spending a lot of time online. Video games, hiding in electronic landscapes, digital landscapes and concern about mental health issues there, et cetera, concern about porn overuse and addiction there, et cetera. But social media itself is an incredible phenomenon to consider in light of everything we're talking about. I can't say, even though I am on all social media platforms and I'm quite active there, I can't say that I've ever been on social media and experience the kind of delight and thrill and persistent energy increase that I experience with in person interaction. And yet social media, I have to assume, is capitalizing on some of these same reward mechanisms in presumably the nucleus accumbens. So are there any data, I realize this is a hard experiment to do in mice, maybe impossible. Are there any data that you're aware of that shows that social media has a high addictive liability? Or do we even need an experiment?

I'm not sure we need an experiment. I think it clearly does. I agree with the point you're making. Although your podcast audience probably doesn't know who I am. I am in my late 60s. I grew up.

Well, they know who you are now.

I grew up before computers, before cell phones. So I still am a believer, perhaps in an old fashioned way, that physical interpersonal reactions are really important. Obviously there are advantages to being able to interact over social media and I mean, for all sorts of reasons. There's a lot of positive and good from that. But back to your question, can we get addicted? I can't speak to social media. I can speak. And Anna Lemke, you know, I think is much more able to eloquently describe the issues around here. I can just talk from my own experience that my cell phone is, and you know, this isn't social media. But checking my email messages, checking my text messages for me has a compulsive, addictive quality.

It's like a lever press.

It's like a lever press for a mouse. And part of that is my own personality. Part of that is the immediate feedback. So you get from a social media post, from seeing your name mentioned, getting a message from one of your friends? Sure, I like getting messages from my friends. It means they're thinking about me. It means I'm part of their world. I have no doubt it's activating my reward circuitry, not nearly to the degree that a hit of cocaine or an opioid would do. So I don't know what else to say about it. I think as a society we have to be aware of these issues and it's really complicated how we manage, especially, you know, once you're an adult, you make your own decisions, for better or worse. But, you know, it's a huge issue, obviously for anybody about it. I, I think as a society, we, we have to be aware of these issues and it's really complicated how we manage, especially, you know, once you're an adult, you make your own decisions, for better or worse. But, you know, it's a huge issue obviously for anybody who has children or.

Is planning to have children and adults on social media. I mean, I see lots of accounts of people that are 18 and older who they spend a lot of time on there. And I'm not necessarily saying that's a bad thing. A lot of people have entire careers that exist on social media. It just seems to me that Instagram, Facebook, LinkedIn, Twitter have.

Who has children or is planning to.

Have children and adults on social media. I mean, I see lots of accounts of people that are 18 and older who they spend a lot of time on there. And I'm not necessarily saying that's a bad thing. A lot of people have entire careers that exist on social media. It just seems to me that Instagram, Facebook, LinkedIn, Twitter have capitalized on this hardwired circuitry, the release of ox. I mean, to make it really reductionist, the release of serotonin, dopamine and oxytocin by virtue of someone saying something to us. Maybe not even a positive thing, maybe it's a negative thing, but as you said, they're thinking of us. There's something about being recognized by others and maybe this is a good seg. We're capitalized on this hardwired circuitry, the release of ox. I mean, to make it really reductionist, the release of serotonin, dopamine and oxytocin by virtue of someone saying something to us. Maybe not even a positive thing. Maybe it's a, a negative thing. As you said, they're thinking of us. There's something about being recognized by others and maybe this is a good seg. We're heading towards empathy here. A discussion about empathy.

I think that's very well put. It is capitalizing on these more primitive neurobiological mechanisms that evolved for purposes of reproduction and survival. I think that certainly has to be the case.

Heading towards empathy here, a discussion about empathy.

I think that's very well put. It is capitalizing on these more primitive neurobiological mechanisms that evolved for purposes of reproduction and survival. I think that certainly has to be the case, and I think it's important. I mean, thank you for bringing that up for us as a society to be at least aware of this. And it doesn't mean it's like many things. It's not all good, it's not all bad. There are positive uses of social media I can see. But, you know, I think it's important. I mean, thank you for bringing that up. For us as a society to be. Mostly, we read about the dangers of it. We read about these kids who are socially isolated.