Full episode transcript below. Beware of typos!
Nick Jikomes
Christian Luscher, thank you for joining me.
Christian Luscher 4:00
Hi, thank you. Thank you for having me.
Nick Jikomes 4:04
Can you start off by just telling everyone who you are and what you do?
Christian Luscher 4:08
So my name is Christian Lucia. I'm a neurologist and professor of neuroscience at the University of Geneva in Switzerland.
Nick Jikomes 4:17
And what is your lab focus on?
Christian Luscher 4:21
So our lab is interested in the neurobiology of addiction. So we would like to know what happens in the brain if you take an addictive substance, such as cocaine or any of the other like fentanyl or any of the opiates. So we would like to know how they act in the brain and what eventually how they change the behavior in those people who become addicted.
Nick Jikomes 4:46
And as a neurobiologist, how do you think about what addiction is? How would you actually define it?
Christian Luscher 4:53
So for us, I mean, there are many different definitions of addiction. We use a very simple one which is this Essentially, the consumption or the seeking of a reward, despite negative consequences. So we have animal models, all the research we do is in mice, we have animal models where we have mice that continue seeking a drug reward, despite the fact that they have a negative consequence, for example, a puff or light electric shock.
Nick Jikomes 5:28
I see. And whether we're talking about lab mice or lab animals, or humans, what distinguishes an individual that becomes addicted when they're exposed to a given drug multiple times versus one who does not? How often in very general terms, depending on the drug, I assume it varies, but how often how common is it population for someone to progress to addiction versus not do that.
Christian Luscher 5:54
So actually, the majority of people can use addictive drugs recreationally without ever losing control. So clinical studies indicate that for the human population, this is about one out of five, who eventually will become addicted. And a similar proportion is also observed in rats, by colleagues of ours, in Bordeaux, for example, and now also by us in mice. And we see that about 20% of the animals who have the opportunity to self administer a drug, and then have to endure this stress of being punished when they use the drug that is about 20% of the animals that eventually will fulfill the diagnostic criteria of addiction.
Nick Jikomes 6:38
So that's a similar number in both laboratory rodents and humans, is that how much variability is there from drug to drug? Is that specific to some drugs? Or is that generally hold across addictive drugs.
Christian Luscher 6:50
So the number I gave you as a drug is for cocaine. So one out of five, cocaine use eventually will become addicted. Obviously, for other drugs such as cannabinoids or cannabis, it is lower. And for alcohol is even lower, but probably for opiates is a little higher than cocaine. So it is sort of a mix between different drugs. And it ranges for maybe, you know, only a few percent for alcohol, up to 30% for opiates.
Nick Jikomes 7:25
I see so so a drug could be considered the most addictive drugs such as cocaine or opioids, are going to result in approximately 20 to 30% of individuals who use recreationally transitioning into a full addiction.
Christian Luscher 7:38
That's right.
Nick Jikomes 7:41
And how much of that susceptibility versus resilience? Can you talk a little bit about the factors that determine that how much of it is genetics and predisposition? And how much of it is other factors?
Christian Luscher 7:53
Yeah, so actually, this is really one of the focus of the current focus of our lab, we would like to understand how this separation between the compulsive individuals and the ones that can recreational use the drug come about? And this is a very difficult question. So the first step that we took is to establish this bimodal distribution in a population of mice. So we were able to generate mice who have eventually really become compulsive. And in these mice, then the first question was to see what is different in their brain compared to those that gave remaining control. So we looked into different circuits, and we found one circuit that clearly segregates between the two sub population, which is the connection between the orbital frontal cortex and the central part of the dorsal striatum. And if this connection is getting stronger, then we can see that compulsion emerges. To the extent that this is actually a link of causality. We have been able to do experiments where we asked officially strengthen that connection. Such an ad that leads to compulsion in animals that initially are not compulsive. And we can do the converse, we can take animals that have a very strong connection there. And we the potential that connection, and the animal will lose its compulsion.
Nick Jikomes 9:28
So is the idea here that you've got a population of animals, a subset of them are predisposed to developing compulsive drug behavior? And what seems to correlate with that is the strength of the circuit going from one part of the brain to another?
Christian Luscher 9:45
Yeah, so there's essentially three levels of trying to understand this. So we would like to know how it is induced, where it is expressed. And then what is the predisposing factor that makes the induction more likely So we do have a fairly good answer to the site, the Loke was very dis expressed this precisely this connection between the orbital frontal cortex and the dorsal striatum. We are now looking into when exactly in the process of the consumption of the drug and the exposure to the punishment, this strengthening emerges. And then the toughest question is remaining for the next years, which is, how is what's the vulnerability? What's the individual vulnerability that triggers that the whole process? And that is that is arguably the most difficult question.
Nick Jikomes 10:40
I see. So we don't know the answer to that last piece in detail yet. But do we know anything about the overall heritability of compulsive drug seeking? How heritable is this from parent to child?
Christian Luscher 10:51
Yeah. So it is interesting to know that, as you already pointed out, the proportion of individuals who are addicted will become addicted, is very similar in a human population compared to a mouse population, despite the fact that obviously, genetically a human population is much more diverse than an inbred lab mouse population that is virtually clonal. So we don't believe, actually that it is sort of hard coded genetic differences. But it is more epigenetic differences that emerge based on life experience. So for that, that's, that's sort of the overarching working hypothesis that we currently have. And experiments that are on the way, try to aim to see what might be different in expression transcripts of a cell in the circuit that we know, ultimately, then is responsible for the compulsive behavior.
Nick Jikomes 11:59
I see. So with cocaine, you have this 20% Number, approximately 20% of individuals, whether it's mice, or humans will, when exposed to the drug become addicted. But because humans genetically are so much more diverse than mice who in the laboratory are bred to be very homogenous, that kind of tells you that it can't be this proportion of the population that becomes addicted. It can't be due to hard coded genetic factors, it has to be something else.
Christian Luscher 12:29
Absolutely, yes. This is a good summary of what I just said. Absolutely.
Nick Jikomes 12:34
Um, one distinction that gets made in the literature by by you and others that I think is important to delineate for people is the difference between drug seeking and drug taking behavior. Can you talk about those two that distinction and why it's important.
Christian Luscher 12:50
So this is a distinction that Barry Everett has introduced to the field. And it distinguishes the compulsive nature of taking a drug, as opposed to kind of the compulsive nature of seeking the drug. And it is true. And that's the argument by Barry, that drug addicts are more concerned about the seeking and the taking itself than actually is sort of a secondary step. And so this is a difference that we and others have looked at. And we find, however, that the core element of the compulsion also resides in this orbital frontal to central part of the dorsal striatum. So this part of the circuit is actually shared between behavior that is, it looks into compulsive seeking, and compulsive taking of the drug.
Nick Jikomes 13:45
So drugs, so in a real world situation, drug seeking, in simple terms would be like, you know, if you're going to the part of town where the drug dealer hangs out, and you're looking, you know, you're looking for the excitement, or whatever, of actually getting the drug. And that's distinct, to some extent from the actual effects of taking the drug itself.
Christian Luscher 14:04
Absolutely. So there is good evidence that different parts of the brain ultimately drive these two different behaviors. But the compulsive nature of those two actually share an overlapping circuit.
Nick Jikomes 14:18
And you've mentioned already a couple times two parts of the brain, the orbital frontal cortex, and the striatum. Can you break down in very simple terms, what we know about these two parts of the brain, very generally speaking, what kinds of behaviors do they tend to be involved in?
Christian Luscher 14:34
So, I mean, probably it makes sense to take a step back and look at the initial target of addictive drugs. So all addictive drugs initially act on the mesolimbic dopamine system, which has its origin at the tiny little nucleus at the tip of the brainstem called the ventral tegmental area. This is a nucleus that eventually at that moment, Has the dopamine neurons and projects to what is called the ventral striatum or the nucleus accumbens. And this dopamine in the nucleus accumbens, then modulates and changes, synaptic transmission that arises from cortical inputs. So from the prefrontal cortex, the hippocampus, and other parts of the brain and when those afferents are active at the same time, as dopamine is massively released through the exposure to a drug, then the synaptic strength changes at these synapses. And if that happens in a repetitive fashion, then the whole process gets sort of shifted from ventral to more dorsal parts. And that's when we arrive in the dorsal striatum, which is a big area in rodents, it's a little smaller in humans, but it has many functions, one of which is related to motor execution. But it also has a role in controlling habits. So actions that we just do automatically. It has a role in goal directed behavior actions that we plan and we really work towards obtaining it. And they're asked in the ventral striatum, we have the top down cortical control. And one of the core policies that controls the dorsal striatum is the orbital frontal cortex, the part of the cortex that just sits above the eyes of an individual, which is why it's called orbital frontal.
Nick Jikomes 16:43
I think an important distinction that you just mentioned is between habitual and goal directed behavior. Can you unpack that a little bit more for people and and which of these and just sort of repeat and unpack which parts of the brains under normal conditions even for a non addicted person, which parts of the brain are responsible for habitual versus goal oriented behavior?
Christian Luscher 17:04
Yeah, so we have essentially three types of behaviors we're interested in, in the context of drug addiction, there's the goal directed behavior. So this is behavior that we plan and we have a goal that we want to achieve, then there is a picture of behavior, that is a behavior that becomes automatic, and sometimes even without being conscious is executed. And the third one is compulsion, which is either an extreme form of habitual behavior. So it is a habit that we can no longer get rid of, even if we want to, or it is an extreme form of goal directed behavior, where only this one goal counts, and all others are disregarded. And all of these sort of are actually coded in cells of the striatum, in the dorsal striatum in particular, with some subdivisions that, however, are to some extent, overlapping.
Nick Jikomes 18:07
I see. So goal directed behavior is like a behavior that we think about we plan it out, we have a goal in mind, and then we we do something to try and achieve that goal. A habit is more or less unconscious, we sort of just do it repetitively without thinking about it. And when either of those behaviors becomes very extreme, it can result in a compulsion.
Christian Luscher 18:29
Absolutely. So an example of a habit is the person who smokes a cigarette and opens a package, lights the cigarette and start smoking without even noticing that she or he did that. A goal directed behavior in the context of drug addiction may be someone who is, let's say, even incarcerated and has a very specific plan, and are they over days and really plans to achieve seeking the drug and eventually obtaining the drug, which may go through many different steps. And that would be an example of a goal directed behavior. So clearly, from these examples, we already see that in drug addiction, both actually do play a role.
Nick Jikomes 19:12
I see. And then, you know, you had mentioned this, this very interesting part of the brain that has a lot of dopamine neurons, and dopamine is somehow involved, or it's very involved in the process of addiction. And it sounded like you were saying that the dopamine is having a modulatory effect. And and what that to mean was, it's able to, it's able to change circuits such that whether or not a behavior is being mediated by one circuit or another sort of shifts that can sort of push it say from being goal directed to habitual or perhaps in the other direction as well. Is that Is that a good way to think about it?
Christian Luscher 19:49
Absolutely. So I mean, the different schools in the in the field of neurobiology of addiction so there is a school that says that we can explain drug addiction by changes in dopamine signaling in itself, first, I have to say that probably everybody agrees that the defining commonality of addictive drugs is that they increase dopamine. Now, those who say it is eventually then the changes in behavior are mediated by a decreased dopamine signaling, for example, because they're lower amounts of numbers of a certain dopamine receptor. And Nora Volkoff has very good evidence for this kind of scenario. And on the other hand, there are others who say, well, actually, what happens is sort of a sensitization of the whole circuit. And that then eventually leads to signaling that is exacerbated. And and so there are other people who say this, for example, unwell, Samaha, and Terry Robinson are defenders of that sort of hypothesis. And we have, on the other hand, look, neither on the down nor on the up, but rather on the sideways. So we found the most compelling evidence in our experimental approach was to show that dopamine actually doesn't change that much in its signaling. But it leaves a trace on glutamatergic transmission, precisely from cortex to the striatum. So when dopamine is very high, and these efforts are active, they change their efficacy, they become what's called potential. And that potential ation, then has an impact on behavior. So this is sort of buying into the idea that the core of drug addiction is what we call drug evoked synaptic plasticity. This is a term that goes back to the early 2000s, where Mark Angliss and Rob Malenko, his lab was able to identify a first form of drug evoked synaptic plasticity by simply looking at glutamatergic transmission 24 hours after first injection. And what he saw is that in the neurons of the ventral tegmental area, when they receive glutamatergic inputs, that input becomes strengthened after the exposure to drug regardless which drug it is, as long as it increases dopamine, which we said is the finding commonality. And that from there on, we and others have been described many other forms of drug evoked synaptic plasticity, not only in the ventral tegmental area, but also in the accumbens and lately in the dorsal striatum. And then by looking at exactly when they arise and how they arise. And what happens if one manipulates the synapses, we were able to map the synaptic changes to specific elements of the adaptive behavior.
Nick Jikomes 23:00
So it sounds like it sounds like perhaps, you know, when you when you take a drug or when an animal takes a drug, you have the the drug evoking changes in the dopamine system, but it almost sounded like whether or not the animal progresses to a compulsion or to addiction might depend very strongly on what happens in the animal in the hours or days after they take that drug, not not even necessarily when the drug is in their system. But what's happening afterwards, is that accurate?
Christian Luscher 23:28
Well, actually, it's it's triggered at the moment they take the drug, but the repercussions are visible afterwards. So it is really this idea of the drug leaving a trace behind after it's been cleared from the brain. So that I think there was when we first saw that, that we can actually look into the brain by probing the strength of synapses, that we can tell with certainty whether the animal has been exposed or not, to cocaine, for example, I found that very interesting. And when then, we realized that this is not only something specific to cocaine, but to all addictive drugs, then we really started working on this very intensely. And we went even a step further, and we sort of replaced the drug by a stimulation of the dopamine neurons itself. So rather than using a pharmacological agent to activate these neurons, we use the optogenetic approach that as we put child rhodopsin into the dopamine neurons, gave the animal the control over the laser to activate these dopamine neurons. And when we did, so we actually ended up with a super addiction. So the essence of the drug addiction can be really reduced to this self stimulation. And when we do that, we find all the adaptive changes in the synapses as well as the behavior and ultimately end up with a three times as many compulsive animals compared to cocaine. So in other words, 60% of the animals that can self stimulate the VTA dopamine neurons eventually are compulsive.
Nick Jikomes 25:14
I see. So if you take a group of lab mice, and you give them cocaine, about 20% of them will become compulsive cocaine seekers. And they'll, you know, constantly want to press a lever to get more cocaine or something like this. But when you have so, when you create lab mice that are specially engineered so that you as the experimental scientist can turn on those dopamine neurons in the particular part of the brain above the brainstem that we're talking about, the animals will then press a lever, and instead of getting cocaine, it will just cause those neurons to become active, and that's super addicting. So 60% of the animals will then just compulsively light up those neurons.
Christian Luscher 25:55
Yes, absolutely. So it's in the ventral tegmental area. And when you stimulate them in the animal has the opportunity to self stimulate, we don't even do that. So the animal presses a lever, and that leads to a dopamine release that is massive, and eventually to a transition towards compulsion in 60%. of the animals.
Nick Jikomes 26:15
Hmm, interesting. So we've talked about dopamine and the VTA, the ventral tegmental area. So far, we've talked about the striatum, which sounds like the part of the brain that is very much involved in selecting which actions the animal is going to do whether or habitual or goal directed. And you've mentioned the inputs to that area from the orbital frontal cortex. So can you talk to us about the orbital frontal cortex, what is it generally doing in a normal animal? What happens, for example, when you lesion that area of the brain,
Christian Luscher 26:47
so there is much evidence that suggests that the orbital frontal cortex codes for the decision that an individual takes, so it's sort of a center that weighs the benefit and the cost of an action, and then according to that equation, will guide the striatum to select the action that needs to be done. So in that's, in a nutshell, the one of the functions of the orbital frontal cortex,
Nick Jikomes 27:19
I see. So you can create animals that are either a subset are either addicted to cocaine are addicted to simply causing their dopamine neurons to fire. What happens if you then withdraw that stimulus from those animals, what happens when you remove either the cocaine or the ability to self stimulate the VTA neurons?
Christian Luscher 27:41
So you're now talking of what happens if the animal gets into withdrawal. And there are major differences between the type of drug that we're talking about. So, opiates, in particularly, will really will lead to a very strong withdrawal syndrome, and that is what defines actually dependents, so we be clearly distinguished dependents from addiction. So dependence is defined by the appearance of a withdrawal syndrome, an abrupt termination of the exposure to an addictive drug. And that again, works through entirely different circuit and has little to do with the ventral tegmental area or the orbital frontal cortex. So this is a sort of a specialty of opiates, it happens to a much lesser extent, also with cocaine. So there are circuits that we and others also study, which mediates sort of this aversive element of no longer having the drug. And obviously, an individual would like to avoid that, which is why we call this negative reinforcement. So the avoidance of this negative state derives further consumption through a different set of circuit compared to the ones we described initially, which are in a originates in the ventral tegmental area, which really is the positive reinforcement. So it's the seeking of more reward, whereas the other one is the seeking of avoidance of aversive states.
Nick Jikomes 29:15
So all addictive drugs have an effect on the dopamine system, but two different addictive drugs can have very different mechanisms of action. And even though they have something in common, they have a lot of divergent properties in terms of what's driving the addiction. And it also sounds like you're making an important distinction between addiction and dependence. So it's possible to be addicted to a drug but not dependent on it. And whether or not you're dependent depends on whether you're going to have these withdrawal symptoms.
Christian Luscher 29:43
Sure, and they're even drugs that make you dependent but not addicted like caffeine. You are dependent on caffeine because if you have if you drink like two three coffees a day and one day you stop you will have I have a headache and that is your withdrawal syndrome. So by definition, you are dependent on coffee. But coffee does not lead to this compulsive consumption that we see with cocaine or fentanyl.
Nick Jikomes 30:13
Interesting. So, so in the case of cocaine and caffeine, you're talking about two different stimulants, but they're both stimulants. Cocaine is addictive. And it does not often cause dependence. Caffeine frequently causes dependence, but it's not addictive.
Christian Luscher 30:29
Absolutely, and it does not increase the dopamine and the mesolimbic system. So this actually turns out to be a sort of a very good biomarker, as long as a substance does not increase dopamine in the nucleus accumbens in the ventral striatum, it's probably safe to say that it has a very low addiction liability.
Nick Jikomes 30:50
I do want to talk to you about some of the differences between different types of psycho stimulant drugs. So on this podcast, I've talked to a lot of people about psychedelics, especially cannabinoids, we haven't talked a lot about stimulants until this conversation. So we've talked about cocaine. So far, you've already told us an interesting difference between cocaine and caffeine, in terms of their addictive and dependency potential. Can you describe a little bit more detail about cocaine and caffeine and what the different sort of mechanisms might be that explain that difference?
Christian Luscher 31:24
Yes, but first, I guess it's really important to make the distinction between psychedelics and addictive drugs. So LSD, and psilocybin and other psychedelics are not addictive. So, these are not substances that induce that state of compulsion and again, are not substances that increase dopamine in the mesolimbic system. So that is an important distinction, then within the, you know, stimulants, there are some which are addictive, such as cocaine or amphetamine or, or ecstasy to a lesser degree, and others that are not addictive, like caffeine that you just mentioned, and that has to do with their molecular target. So it is not trivial task to explain how this relatively large group of addictive substances, and depending on how you define them, we're talking between 12 and 20 different types of substances, how they would converge on to having one defining common final pathway. And so, we have spent quite some time to try to understand how this comes about. And we know for example, we know the molecular targets of most of them, we know that cocaine targets monoamine, transporters, dopamine, serotonin, norepinephrine, and it is clear that if you take out the dopamine transporter, the binding of cocaine to the dopamine transporter, you end up with a non I mean, in these in these transgenic animals, cocaine can no longer induce compulsion. So this is, you know, the, the really dissection to the molecule of how the whole process starts. Now for opiates, it's the new receptors among the three receptors, that is really important. And if you knock out the new receptors, then all addictive properties of opiates are gone. So there are a number of things and that it breaks them eventually down into three different mechanisms. So either a drug directly activates the dopamine neurons in the ventral tegmental area, that's the case, for example, for nicotine, or it works, as I said, like cocaine does by blocking reuptake. So since Dopamine is a somewhat expensive molecule for the brain to produce, there's a sort of very nice recycling path in place. And if that gets blocked, because the reuptake is pharmacologically Bach, then dopamine increases. And the last mechanism, the third one is an indirect one, where the drugs don't actually work on to the on the dopamine neuron, but they work on GABA neurons, which are upstream of the dopamine neurons and normally inhibit those dopamine neurons. And when these trucks work on those, they shut down the activity of the GABA neurons, which usually inhibits the dopamine neurons and the resulting disinhibition leads to an increase of dopamine. And examples of drugs that are part of that class are the opiates and cannabis.
Nick Jikomes 34:44
I see. So if we take it, let me try and summarize that. So multiple addictive drugs ranging from cocaine to nicotine to opioids, they all alternately converge on the fact that they can increase dopamine levels, but some of them do that directly. And some of them do that indirectly. And there's very different pathways, very different mechanisms they can take to actually achieve that final common end. And the details distinguish sort of both the subjective effects and also the propensity to actually become addictive.
Christian Luscher 35:18
Yeah, absolutely. So this is this is a very good summary. And it is just it's important to realize that they really sort of all converge on to that system. And it's also important to realize there was still a couple that we don't exactly know how they how they work, and the most prominent is alcohol. So alcohol clearly increases the dopamine, it is addictive. We all know that. But we don't have a good molecular explanation how it increases the dopamine. And that is largely explained by the fact that it has so many molecular targets, you know, unlike opiates, really, that only have three receptors in the brain. Alcohol binds to a plethora of different receptors. And so it's very difficult to dissect that entire molecular mechanism.
Nick Jikomes 36:08
So going back to psychostimulants for a minute, we've we've touched on cocaine, nicotine and caffeine, each one has a different level of addictiveness. You've already mentioned that caffeine is actually not addictive, but you can become dependent on it. cocaine and nicotine are both addictive, but they act in slightly different ways in terms of how they affect the dopamine system. Is there like an overall besides this the general subjective notion that they're stimulants and they sort of wake you up? Is there? Is there a good unifying way to think about what makes a drug a stimulant, as opposed to another type of drug?
Christian Luscher 36:44
No, as you probably just said, I mean, it is a drug that makes you more alert. And so you know, norepinephrine, there are different systems that can do that. And they all have in common that you do. So you have to sleep less. And yes, maybe also modulate your direction system could be defined a stimulant. So yes, that's, that's a good definition.
Nick Jikomes 37:09
One other type of psychostimulant that I wanted to ask you about, and I'm not sure if this is your specific area of expertise, but I assume you can tell us a lot of valuable information here are prescription stimulants. So as I think many people know, at this point, things like Adderall and Ritalin are very widely prescribed. I know many people in my own life who have prescriptions that are prescribed to adults, they're prescribed to adolescents and even children. How does Adderall or prescription amphetamine like this work in comparison to these other psychostimulants? And then, are they addictive? And can they cause dependency?
Christian Luscher 37:44
Yeah, so there are there's a number of maybe half a dozen of different molecules. Modafinil is another one of those, and they do clearly have effects on mono amines. Again, their pharmacology is very complex. I do not know all the details of all of those, but it is clear that some of them do have an addiction liability. So Modafinil, for example, seems to, you know, not as strong, some Fetta means, but it is clearly also an addictive substance. So it is again, the sort of the profile of which of the mono Amin they increase most that it has as a as an impact on how addictive they actually are.
Nick Jikomes 38:29
And what's the role of developmental timing in in defining the probability of transitioning to compulsion? My guess would be that the earlier on in life that you expose an animal to a potentially addictive drug, the more likely they are to transition to such a, a compulsive state?
Christian Luscher 38:46
Well, clearly from the clinical literature, we know that there are some critical periods of drug addiction and adolescence is generally recognized to be one of the critical periods, probably even also old age to some extent can be a critical period where people are particularly vulnerable. And we have to model this also in animals in order to have a better mechanistic insight. I'm not aware of sort of a unifying hypothesis that fully explains it has a lot to do with the control of the prefrontal cortex of the ventral striatum, that is one of the routes that others are pursuing in order to understand how exactly this vulnerability comes about.
Nick Jikomes 39:36
Interesting. So we've mentioned dopamine a lot so far, and I want to talk about it just a little bit more before touching on some other transmitter systems. You've done a nice job of explaining a lot of the details so far, the thing that I I always hear people say and I remember learning this in school, even in grade school, is they would talk about they would use a metaphor of, you know, a drug hide jacking your dopamine system. So a lot of people will be familiar with that. That imagery. Do you think that's a fair way to for someone who doesn't have a science background to start to think about addiction? Or is that incomplete in some important way?
Christian Luscher 40:12
No, I think it's it's a good image of what actually happens. So hijacking in the sense that this is a stimulation that is stronger than a stimulation in response to a natural reward. And it is hijacking because even if dopamine goes back to baseline, there are circuits in the brain that are changed. And that eventually, when they built up can lead to altered behavior, and eventually addiction in some individuals. But I guess in order to better understand this, it is probably helpful to go back and ask a little bit, what is the physiological role of the neurons in the ventral tegmental area. And this is actually a matter of much debate. So there's a lot of colleagues who work on that. And we also have done some of the work. And as always, it's more complicated than what we initially thought. But I guess it's fair to say that there's still one function that, under some circumstances definitely is present and is very important. And that is this function of reward prediction error. That is, these cells code for the difference of what one expects as a reward and what you actually obtain. And so if you receive something a big reward out of the blue by total surprise, that's something you didn't expect, that strongly activates the dopamine neurons in the VTA. If on the other hand, the reward is entirely predicted, let's say, I don't know your salary at the end of the month, this is something that you were promised and you receive it. And so there is no prediction error, because you receive exactly the amount that you were promised. So at that time, the sales will not react. If on the other hand, you are promised a reward, but then you don't receive it, then there's a negative prediction error. So you were expecting more and you receive less, and that shuts down the system. And these differences have then been conceptualized as a learning signal. And that's really interesting in the context of predict drug addiction, because it means that what the drugs actually generate is a pathological learning signal that leads to a maintained prediction error that eventually drives the behavior into something very narrow, and only linked to the seeking and to taking off the drug. I see.
Nick Jikomes 42:55
So these neurons are in effect, encoding surprise.
Christian Luscher 43:00
it to some extent, yes, surprise, but surprise, of receiving a reward. That's the initial postulate by Wolfram Schultz. And he has made these initial observations in 1998, I believe, published maybe a year or two later. And that really has been very influential in conceptualizing the role of these dopamine neurons, by now using higher resolution techniques and being able to follow these cells in more naturalistic behaviors. And during the entire phase of the training, we know that everything is a little bit more complicated that to some extent, they even also code for movement. They code for sometimes for saliency, so independent of whether it's a reward or a punishment, and then there seem to be even dopamine neurons that are specialized to respond when one receives a punishment.
Nick Jikomes 43:56
I see. So dopamine neurons are not all the same. There's differences among now
Christian Luscher 43:59
they're not all the same. So there's clearly differences among the dopamine neurons, and it depends exactly where they're located in the ventral tegmental area and where they project to.
Nick Jikomes 44:09
I see. I want to ask you another question about withdrawal. And in general, so let's say you get an animal addicted to a substance that it becomes dependent on and then you take the drug away, and the animal goes into withdrawal. If abstinence is maintained, will the circuits in the brain that were underlying the addictive behavior and the dependency naturally sort of revert back to their their prior state? Or does there have to be like an active unlearning process there?
Christian Luscher 44:45
So for the addiction part, clearly there has to be an A duck, an active and learning part to it, or dependence, it's less clear. And the observation is that after all, Maximum 72 hours, the entire withdrawal syndrome is gone. And then we basically start from zero again. But the addiction part, it is equally clear that individuals who have been abstinent for prolonged periods of time still have an increased risk of relapsing compared to someone who has never been exposed to a drug.
Nick Jikomes 45:24
Turning now to another class of drugs that I'd like you to briefly comment on. You very briefly mentioned it earlier, but we've talked about psychostimulants, we've touched on opioids and alcohol. You mentioned cannabinoids earlier. So if we focus on the principal cannabinoid in cannabis, which people are consuming recreationally THC, what is the sort of addiction and dependency liability for THC, and what kinds of mechanisms might distinguish this drug from cocaine say?
Christian Luscher 45:54
Yeah, so this is obviously a very interesting molecule. And it binds to receptors that we know well. So these are the so called CB one receptors, which are coupled to G protein, this is the big big family of receptors in the brain, they all have the same structure, and they all control G proteins. And in particular case of the CB one, it's the GI O type of G proteins that are activated. And it is part of the class of drugs that works indirectly. So the primary target of the THC is actually the GABA neurons in the ventral tegmental area. And what cannabinoids are the cannabis does, they are the THC. It binds to receptors both on the cell body, as well as on the terminal of the axon that is releasing the GABA onto the dopamine neurons. And two different molecular mechanism, they lead to a shutting down of these Governor neurons. And they block the release of GABA. And so basically, this governor is taking out and as a result, the dopamine neuron is this inhibited. So what makes now so this is the sort of the basis of addiction to THC. What makes this drug, even more I would say problematic is that it interferes with a endogenous system. So a system that the brain has itself of so called endocannabinoids. So they're not exactly THC. But there's something similar that also binds to the CB one receptors. And basically what this what these endocannabinoids do in the brain, they fine tune all synaptic communication between cells. It is typically a neuron, but the called postsynaptic. So the neuron that receives the information that releases these endocannabinoids, that then travel back on to the axons of the cell that sends the information and controls the output of that cell in a very, very fine tuned fashion. And so if people smoke THC, then of course, all this fine tuning disappears. And this fine tuning is really important for a lot of forms of learning, which explains why people who smoke a lot often have problems at school.
Nick Jikomes 48:31
So what is the addiction potential for THC relative to something like cocaine?
Christian Luscher 48:37
Oh, it's definitely lower that that is that's obvious. So it's roughly around 10%. But with recreational use over the years, then you end up with with with 10% of, of HD users that eventually have a problematic compulsive use.
Nick Jikomes 48:57
I see. And then what about dependency can you become dependent on THC?
Christian Luscher 49:02
Well, to some extent, but I think it's not a very strong stereotypic withdrawal syndrome. Yes, they do have some, but it's not comparable to a opiate withdrawal.
Nick Jikomes 49:15
So turning now to I want to talk about another transmitter, serotonin, I know that you've done some work on serotonin in terms of its role in addiction. You mentioned earlier, the key fact about psychedelics which is that they're non addictive, and as many people who've listened to some of the previous conversations I've had on here will know psychedelics are known to activate certain serotonin receptors in the brain. Is there any tie in there is that have something important to do with the fact that they're non addictive and then more generally, what is the role of serotonin in this whole addiction process?
Christian Luscher 49:51
Yes, so clearly, drugs that work on serotonin system are not addictive, and probably the most often used prescribe drugs are the SSRIs selective serotonin reuptake inhibitors like citalopram. And what they do is they block these the reuptake of serotonin and through that increase serotonin in the brain, and this is mostly the indication is mostly depression. So they do have, in some people a very beneficial effect for that, and do not induce addiction nor dependence. And so that that is clearly different and in for the psychedelics. It's not the transporter, but as you rightly pointed out is some specific receptors that are activated. And of course, that leads to a totally different experience, which can result in a very strong distortion of perception. So people see color differently, forms, shapes, or hear things that don't exist. So this is the, if you will, the appeal for some people to take psychedelics. Now, what could be the effect of serotonin on the addiction process, and particularly the transition from a controlled recreational use to a compulsive use. And this is indeed, a study that we have just recently published. And it was sort of inspired by work out of several labs with doing behavioral pharmacology that were suggesting that somehow serotonin might actually be breaking meaning making the transition less likely. So we took a approach in our mouth in our animals by generating a transgenic mouse that had a serotonin transporter that no longer bound cocaine, because cocaine, as I said, increases dopamine but also increases serotonin. So in these mice, we now have cocaine increasing only dopamine, but not serotonin. And when we looked at the transition to addiction, we realized that it is not 20%. But now it's 60%. Of the mice of the cohort that eventually become became compulsive. So there we had it. So we had evidence that yes, indeed, serotonin sort of makes the transition towards compulsion less likely. So in order to really Yes,
Nick Jikomes 52:33
the experiment you just described, it's reminding me of your previous finding with the optogenetic self stimulus stimulation. Yes, it's
Christian Luscher 52:41
so it's exactly now we could actually do the second experiment, where we would do a pure dopaminergic type of addiction, that is our self stimulation of the VTA dopamine neuron. And now what we can do is we can use SSRI, like side citalopram to artificially increase the serotonin level. And when we do that, we dropped from the 60% of dopamine or on self stimulation to only 20% in dopamine on self simulation, plus citalopram. So we had it sort in both directions. And from there on, we did isolate the circuit. And we identified again, that it was this OFC to central part of the dorsal striatum that was responsible for that. And that serotonin through a very specific receptor, did control whether that connection became stronger or not. And so when serotonin is here, that connection is less likely to become potentially rated, which is why we only have 20%. And if serotonin cannot act on that receptor, we are up at 60%.
Nick Jikomes 53:54
I see. So So compulsive addictive behavior involves this critical circuit going from the orbital frontal cortex to this place called the striatum, and whether or not that connection strengthens. And one of the key determining factors, it seems, is both the level of dopamine and serotonin.
Christian Luscher 54:13
Yeah, so dopamine pushes towards strengthening and serotonin makes that strengthening less likely. And so it dopamine therefore pushes towards compulsion where serotonin is making this less likely.
Nick Jikomes 54:29
So you mentioned that you were effectively giving lab mice SSRIs in these experiments, is there any data out there showing that humans who are taking SSRIs are less likely to become addicted to cocaine or other drugs?
Christian Luscher 54:43
I don't think so. Because if you think in humans, which are not transgenic, of course, at cocaine already increases both dopamine and serotonin. So that increase is already maximal and You cannot add by taking an SSRI at the same time. So I think that is explains why it is not a good prevention strategy to take necessary along with cocaine,
Nick Jikomes 55:14
I see could that conceivably work in in the 20% of people that do transition to compulsion, if it's true that the reason that they are part of that 20% is some sort of deficit in the serotonin increase?
Christian Luscher 55:26
This is a very appealing hypothesis that we're now pursuing. Yes, that could be one of the many possibilities why a endwall is more vulnerable. This is indeed interesting. And it could be that somewhere along the line of the entire cascade of releasing dopamine binding to receptor, the receptor signaling, and so forth, there could be some form of deficit that would make this individual particularly vulnerable to drug addiction.
Nick Jikomes 56:02
So one of the key things that I think that we've discussed so far is, on the one hand, there are many different drugs of abuse, they all have different abuse liabilities, or, or, you know, different tendencies for someone to become addicted or to become dependent on the drug. And that's because they all act through different mechanisms. And there's many different ways that that they can actually affect things in the brain. But at the same time, there is this sort of core mechanism at the center of addictive behavior, which is the ability of a drug tap into this mesolimbic dopamine system. So despite all the differences between drugs, and the mechanisms, there is this sort of common thread, running through all of them. And in that context, I'm wondering if you can talk about addiction to things other than drugs. And so in particular, people have talked a lot about food addiction, or say social media addiction, do these types of addiction? Is that merely a metaphor? Or can you does that truly tap into the same circuitry at the end of the day?
Christian Luscher 57:07
My hunch it, it is the same sort of mechanisms and same overarching hypothesis that would apply to these non substance dependent addictions. Now, obviously, as a scientist to this animal experimentation, we would like to understand the precise mechanism of how this is done. And so so far, that has been more difficult than we thought, because it's not so easy, for example, to get the mouse to gamble. There are some tests where you can do that. And but it's not to the extent that you would make a mouse eventually become a pathological gambler. And it is also it's a very tough thing to do. Because we know that gambling is something that has a lifetime prevalence, pathological gambling have a lifespan prevalence of roughly 1%. So 99% of people can occasionally, you know, gamble a little bit, and they never lose control. And this is 1%, which is eventually becoming addicted. And so how you model this in in a mouse is a very, very tough question. Similarly, for food addiction, it's also it's it's there are there's very good evidence that highly palatable food activates the dopamine system, and that through these mechanisms, things happen. But food intake involves a lot of additional circuits, some of which we've also studied. And it's not a straightforward thing that you can just take what we know from drug addiction to other addictions, there are details that matter that need to be worked out.
Nick Jikomes 58:52
Interesting. So as someone who has been studying drug addiction and addiction for many years, has this, you know, has your research impacted how you think about your own consumption habits in your own life? Whether it comes to food or to technology or anything?
Christian Luscher 59:11
Nah, not really, I'm not the first I probably am part of the 80% majority will not lose control. So I'm actually I'm really separating what I do professionally from what I do privately. So I'm not I'm not particularly inclined in doing any self tests on that.
Nick Jikomes 59:33
So what, what areas of research are you guys actively pursuing right now or what's on the horizon?
Christian Luscher 59:40
Yes, so what I said what really is interesting for us is to try to understand the individual vulnerability before a mouse gets exposed for the very first time for an addictive substance. So this is clearly a big question that we have in the lab. We also need to better understand how drug addiction may extend to other addictions. And the one that we are closest in working on is food addiction. So we have some experiments where we look at circuit that control hedonic food intake. So, intake of food that is not directly motivated, motivated by energy demands. And so you can show in a mouse that mouse will continue taking highly palatable food, even if it exceeds its energy demands. So these are some of the questions we're currently working on in the lab.
Nick Jikomes 1:00:43
One final question in terms of the issue of vulnerability to addiction. We've mentioned this 20% number for cocaine, about 20% of lab animals will become compulsive cocaine seekers. When you give animals that first administration of cocaine, is there anything behaviorally that's different in that very first administration that allows you to predict which ones will then go on to compulsive behavior?
Christian Luscher 1:01:08
We found and others have reported this before us that impulsivity is a behavior that correlates with subsequent addiction, that is animals that cannot refrain of pressing a lever, even if it's during a timeout period, for example, these are the individuals that are more likely to become compulsive in the end. So yes, there are some of the behavioral observations that help us delineate between what's going to happen in the future, but they are not 100%. So we, we need to do better on those. And we're including now additional parameters that will allow us to better understand this.
Nick Jikomes 1:01:53
Interesting. Are there any final thoughts you'd like to leave people with in terms of the general area of research that you focus on in addiction generally?
Christian Luscher 1:02:03
Well, I mean, it is, as probably became clear during our discussion, also as many other fields in the neurosciences something that advances in small steps. So I think it is very important, at least to me, it is that one builds on solid grounds, and that the next experiment sort of touches back with what happens and either confirms or refines the finding of previous experiments. So throughout the entire now 20 plus years that I had my lab, I always tried to sort of build this one step at a time. And I think that is that is, for me something very important. It is also important for me to say that all of that can only be achieved, because we can still do animal experimentation. And that is not something that is a given. And there, the rules and requirements to do so become more and more complex. And this is probably something that is also important for the public to know that should we no longer be able to do animal experimentation, it would be very difficult to progress in this steps towards something that eventually obviously, long term goal would have an impact on human treatments. So it's sort of a translational way of of doing of doing the research, we have ourselves tried a little bit to endeavor in some of these translational aspects. And one idea that we developed in our lab is to look how we could emulate what we learned from optogenetics to use with therapy methods, therapeutic methods that are actually currently used in humans. So rather than trying to translate optogenetic interventions to humans, which I'm sure someday will happen also in these deep brain areas. Rather than doing that, we said why don't we benefit from the knowledge that we have the circuits and how we can encode cure the behavior and restore normal behavior, with optogenetic in humans in animals, whether we whether we can use this to inspire new forms, for example of deep brain stimulation. So you could imagine that deep brain stimulation, which is an electrical form of stimulation can be refined by using it with different frequence and sees in combination with pharmacology or in brain areas where it hasn't been tried. And that this would sort of help you emulate something that you can successfully do with optogenetics. So this is a line of research that I have initiated, and that we are now having meetings, which we call up the BBs and trying to bring together the clinicians who are the specialists for the Deep Brain Stimulation Protocol, who can tell us what can be done. And on the other hand, we have on the other aisle, we have the optic geneticists, who say, this is what we should be doing. And then we try to find solutions together. And this is, of course, for me particularly interesting, because, as I said, initially, I'm not only neuroscientist, I'm also a neurologist, and I do actually see every week for a day I see patients with movement disorders, you know, I'm very familiar with these approaches, like deep brain stimulation. And I really would like to see, during my career, a successful implementation for a new indication based on optogenetics circuit dissection.
Nick Jikomes 1:06:11
Interesting. And for those that don't know, can you just briefly explain what deep brain stimulation is and how it's used today?
Christian Luscher 1:06:19
Yeah, so deep brain stimulation is a form of surgery, where the neurosurgeons implant an electrode electrode into the brain, in the depth of the brain, typically in the subthalamic nucleus for to treat patients with Parkinson's disease. And when this stimulation is turned on, through a little battery that the patient is having under his skin, then the symptoms disappear, such as tremor, or rigidity, and the movement become much more fluid. And this is a technique that has been invented law now 30 years ago, and has is currently used in more than 200,000 patients worldwide. And it is today one of the few interventions that are approved to change circuit function in humans. And so because we now know that addiction is a disease of circuits that work the way they shouldn't be working. One can say that maybe there is a way to correct this pathological function through electrical stimulation.
Nick Jikomes 1:07:33
Interesting, well, Cristian Lucia, I don't want to take too much more of your time. Thank you. This has been fascinating. I think we covered a lot, a lot of ground and people are gonna find this very interesting podcast.
Christian Luscher 1:07:44
Okay, thank you so much, Nick, for having me. And yeah, thank you and have a nice
Unknown Speaker 1:07:50
day.
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