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Christian Lüscher: How Does Ketamine Work & Is It Addictive? | #90

Full auto-generated episode transcript below. Beware of typos!

Nick Jikomes

I am good. Can you remind everyone who you are and where you're located?

Christian Luscher 4:48

Yes. So my name is Christian Lucia. I'm a neurologist and neuroscientist at the University of Geneva in Switzerland. And over the last 20 years I've led a lab into ested in the mechanism underlying the neurobiological mechanism underlying drug addiction,

Nick Jikomes 5:05

and you've got some recent work that's out about ketamine, and we're gonna get to that. But I thought maybe a good starting point would be some basic biology for those that don't know it. So when you talk about a drug that is addictive, what specifically does that mean? And what parts of the brain and circuits in the brain do we tend to focus on for addictive drugs?

Christian Luscher 5:28

Yes, indeed. So we work in mice, and that allows us to make observations that are typically not possible in humans. So over the last 20 years, we have looked at many different elements of what addictive drugs do in the brain to start, we realize that addictive drugs converge on to a one specific system that called the mesolimbic dopamine system that extends from the ventral tegmental area to the nucleus accumbens. And it is a system where the the majority of cells are dopamine neurons. And when drugs hit the brain, that this dopamine is massively enhanced. So there is an increase of dopamine, particularly in the nucleus accumbens, but also in the ventral tegmental area. And that is sort of the initial trigger that may lead to addiction in some individuals. So this is the first step. The second step then is that this dopamine that increases has an effect on glutamate transmission in the target region. In the nucleus accumbens cortex sends extensions to the neurons in the accumbens. These are glutamatergic excitatory neurons, and their efficacy, how they activate these neurons in the accumbens changes as a function of dopamine in some cells, that increases the transmission and in other, it has a tendency to decrease depending on what type of dopamine receptor T cells express. So this is the first the second step, which is a step of synaptic plasticity, that is, dopamine modulates how glutamate talks to these to these neurons.

Nick Jikomes 7:20

I see. So when you when someone or an animal ingests certain drugs, cocaine, for example, you get this surge of dopamine coming from this place called the VTA, the ventral tegmental area to the nucleus accumbens. And that change then alters how other inputs to that region are operating and then you get physical changes neuroplasticity happening and that leads to behavioral change ultimately,

Christian Luscher 7:47

absolutely. So it is a sort of tripartite organization between dopamine coming from the midbrain up to the striatum, the nucleus accumbens is part of the striatum. And on the other hand, you have cortical top down projections, and if the onto those neurons in the accumbens, and if those three elements talk to each other, dopamine modulates how glutamate can talk to the neurons in the accumbens. So it's a neuromodulatory role of dopamine that is underlying the changes in synaptic efficacy, neural plasticity, as you said, and eventually behavior.

Nick Jikomes 8:29

And so, addictive drugs, drugs that are addictive compared to drugs that are not addictive. They all share this common property affecting the sort of dopamine surge that goes from the VTA to the nucleus accumbens. The details are probably different from drug to drug. But that's

Christian Luscher 8:46

so key thing. Yes, that's the key thing there. There are three distinct mechanism how drugs can do this, they can simply activate those cells depolarize them that become active, or they can as cocaine does it, block the reuptake of the dopamine that has already been released. And the third class is a class that works indirectly not targeting the dopamine neurons, but upstream inhibitory interneurons. And when they are silenced, the dopamine neurons is disinhibited or disinhibited, and that increases the dopamine. So yes, that is a commonality of all addictive drugs. And you can put them to the test with substance that are psycho active, but are not addictive, like hallucinogens. So they do not increase dopamine in the mesolimbic system.

Nick Jikomes 9:38

I see. So all addictive drugs share this property, they can cause addiction through different mechanisms, but they sort of converge at this place in the brain doing with this kind of effect on dopamine signaling and plasticity generally. So not all drugs have that property. As you just said, psychedelics are one example. They work through other mechanisms. We're gonna start talking about ketamine. And so what had been known up until your paper about how ketamine was acting in this mutual limbic dopamine reward circuit.

Christian Luscher 10:10

So before we go to ketamine, if I may, there is a third step that is really important once we have this plasticity accumbens, that's by no means sufficient to already qualify as addiction. This is a step that actually happens in all individuals and drive some of the early adaptive changes that we see with drugs. The crucial step, however, then is when animals are in withdrawals go from a controlled drug consumption to a compulsive drug consumption. And this step is a step that only occurs in some individuals. We know that for cocaine, this is roughly 20%. And we know also that this now requires circuits that are more dorsally located so we we move from the ventral striatum to the dorsal striatum, and when that happens, some individual may become compulsive. So there are three steps the initial triggering of the dopamine search. The second one is the first type of neural plasticity in the accumbens. And the third, then is to relate to the dorsal structures, and only if these three sequences happen, an individual eventually is addicted

Nick Jikomes 11:25

ice. So the first sort of piece in that pathway happens in everyone but then only in a minority of people, do you get the last part happening, which is closely tied to the actual addictive part of this?

Christian Luscher 11:39

Absolutely, then that is a challenge also in the research to understand because we have this one might call it stochastic element to it that some individuals become addicted, and some others will not, despite the fact that they essentially use the same amount of drugs. So it's, it's there is some element to that. And while in the beginning, I struggled to understand this concept, it actually is pretty obvious. Many of us use addictive drugs such as alcohol for an entire adult life, and we never lose control. So there's clearly for these kinds of drugs there are is a majority of people actually can use drugs for prolonged periods of time, and never fulfill the criteria of addiction.

Nick Jikomes 12:24

Is it easy to tell ahead of time, either in humans or in animals, which individuals are predisposed to developing addiction?

Christian Luscher 12:31

That actually is a difficult question. And we do have some behavioral hallmarks, mostly from the clinical literature. We know, for example, that people who are impulsive, who can't wait for some things, they are at risk for being poor becoming addicted and becoming compulsive. So yes, this is there. So at the behavioral level, we have some elements that let us predict, but they are by no means 100%. And at the level of the neural circuits, this is ongoing research, we do not have good markers to predict which individuals will eventually become addicted.

Nick Jikomes 13:11

Okay, so now if we start to think about a drug like ketamine, what was known? You know, is this known to be an addictive drug? Is that something that's been debated and what what was the state of the field up until recently?

Christian Luscher 13:24

So, ketamine is a drug that has been around for many years, it was developed in the 1960s. The main purpose was to generate an anesthetic to some extent, also a drug that would relieve pain. But it also has become clear that it is abused in club settings and for its dissociative properties. So people found this attractive, and there have been occasional descriptions of people who sort of lost control. But there was never a big study to really establish its addiction liability. And recently, however, what has changed is that some really interesting work in psychiatry has shown us that ketamine has this potential of being a rapidly acting antidepressant. And for that reason, many more people have now been prescribed ketamine. And so that question of its addiction liability, has to be reassessed. Since we know it's a stochastic process, not everybody might eventually become addicted. So we have to test this. And our contribution is to use our knowledge about the neural changes in the brain of mice to put ketamine to that test. So we're going to look, you know, first, does it increase dopamine second, does a cause the plasticity and third is it going to lead to compulsion? So that was that's our contribution to to this question

Nick Jikomes 14:59

and was already known or was it unknown whether ketamine causes this dopamine surge in this music Olympic dopamine reward system,

Christian Luscher 15:11

there was contradicting evidence, some people saw a little increase, some people did not see an increase. And I think that is explained largely by the absence of the appropriate tools, we did not have a tool that would with certainty and with the fast temporal kinetics allow us to follow dopamine in the nucleus accumbens and the VTA. And this is sort of how we got into it, this the, these newly developed genetically encoded dopamine sensors that allow us to translate dopamine concentration into fluorescence, and allow us, therefore, to look at dopamine in vivo in freely moving mice in response to a drug or in other situations. And that, for us has been a game changer. And that's how we sort of got into that project, because we could now really measure and visualize dopamine in the areas that matter.

Nick Jikomes 16:08

I see. So you actually have tools now where you can take mice, and literally look inside their brain. And when dopamine is released, released, it literally lights up and you can see it.

Christian Luscher 16:19

Yeah, so these are really, it's a new generation of fluorescent sensors, developed essentially by two labs, Lin Chan at UC Davis and you long Lea packing University. And what they have been able to do is they have to, they took a part of the receptor, the dopamine receptor, made it inert, so it wouldn't signal to the cell but coupled it to green fluorescent protein. And so whenever dopamine binds on to that receptor, it pulls a little bit on that green fluorescent protein, which changes its fluorescence. And you can then calibrate this and you see dopamine increases. And you can see that with very high specificity, and very high sensitivity. And that for us has been really a game changer. This became available in 2018.

Nick Jikomes 17:11

Okay, so this is, this is new technology. That's very exciting. So you have this at your fingertips. And so, what do you see what does actually what is ketamine doing at this critical VTA to accumbens synapse?

Christian Luscher 17:23

Yeah. So what we do we do inject this delight that is called dopamine light and into the accumbens, and put in an optical fiber to monitor the fluorescence, and then inject ketamine. And what we see is yes, indeed, there is an increase in dopamine. But what was very surprising and in amplitude, and how strong it was, was almost comparable to cocaine. But what was very peculiar is that it returned to baseline very quickly, actually, during the time that ketamine was still in the brain. So it had this effect of creating a surge. But that surge was much faster than anything we expected. So that was the first observation.

Nick Jikomes 18:13

And so so if you compare that to something like cocaine, what you're saying is, you see a surge with both drugs, but the surge lasts longer with something like cocaine and it shuts off more quickly with ketamine.

Christian Luscher 18:23

So with cocaine, the surge lasts as long as cocaine is in the brain. And with ketamine, it's faster. And it actually is it stopped, while ketamine is still on board. So the first thing we had to find is what makes that so how is that that search generated? And why is it so fast? So, for that, we then took advantage of other technology that allowed us to look at the firing rate of the self, the dopamine arts, and what we saw is that the dopamine neurons, they did fire more and they were therefore at the origin of the search. But the cause for that was not at the level of the dopamine neurons themselves, but it was because ketamine inhibited the GABA neurons, the inhibitory neurons that are upstream of the dopamine neurons. So it felt in that third class that I described before, of drug that work through this inhibition. Again, the problem we had is that GABA neurons, on the other hand, they remained inhibited, despite the fact that the dopamine surge was terminated, and the dopamine neurons were no longer firing. So we had a partial explanation, but we still couldn't explain why it was so fast.

Nick Jikomes 19:43

Okay, so the dopamine neurons are there. They've got all of these inhibitory neurons, connecting to them that are sort of acting like brakes and preventing the neurons from firing inappropriately when that's supposed to the ketamine is actually dis activating the dopamine neurons indirectly by inhibiting the inhibitory neurons.

Christian Luscher 20:03

Exactly. So this is exactly that this inhibition mechanism that you set up very well.

Nick Jikomes 20:08

And so what else is ketamine doing? mechanistically? And how does that start to tie in to this puzzle?

Christian Luscher 20:14

Okay, so then in order to understand why it's action was terminated so quickly, we actually sort of found out that it hits special receptors on the dopamine neurons that can silence those. These are a type of dopamine neurons at dopamine receptors called D two receptors, which coupled to a potassium channels and hyperpolarize T cells. And it is through that mechanism that we have, that the search is terminated very quickly. So at that point, when we understood this, the disinhibition increase of dopamine, but that dopamine then feeds back on to the dopamine neurons to activate the two receptors and terminates that search. Then we had an understanding of this initial step that happened.

Nick Jikomes 21:06

I see. So ketamine gets into the brain, it dis inhibits the dopamine neurons by inhibiting the inhibitory neurons, you get this surge in dopamine release, but that very quickly shuts off because the ketamine is also inhibiting the activity through these other dopamine channels of the dopamine neurons directly.

Christian Luscher 21:25

Absolutely, yes. So it's a complex that's gave us the idea for the title. It's a dual action. It's an action of dense ambition, but then inhibition again, and that was for us a very interesting thing. So the question was, Is this now a direct effect of ketamine? Or is it that is it the indirect effect through the dopamine? And I think the literature is still open, some people say that ketamine can actually directly activate these D two receptors and other disagree with that. I think that is still an open question. But the fact is that these searches are very fast.

Nick Jikomes 22:03

And so this gives you a very different sort of dopamine release profile and different dynamics in the circuit compared to something like cocaine. And you would imagine that that would affect the addiction liability of the substance. So how do you actually measure that in animals?

Christian Luscher 22:19

Yeah, so the next step, obviously, is, do we see these drug evoked synaptic plasticity is that we typically see with other addictive drugs, and we did a side by side comparison. So injection of cocaine, we had very nice changes in synaptic efficacy in the accumbens. And with ketamine, we didn't see this at all, there was no drug evoked synaptic plasticity. And so that was already indicating that probably, that search was so fast that it was insufficient to do that. Or there were additional mechanisms at play that prevented this, this this plasticity from being induced. And it turned out that it is a combination of both. And so the way we sort of, were able to get at that is by looking at the requirements of inducing that plasticity and one of the key elements of that is a receptor called NMDA receptor, which is a receptor that binds glutamate and is at the beginning of many forms of synaptic plasticity. And it turns out that ketamine actually is a drug that inhibits the NMDA receptor. So that is, it was that the was explaining to us why we don't have this plasticity that we usually see with addictive drugs.

Nick Jikomes 23:47

Yeah, it actually kind of makes a lot of sense. Typically, when you take a neuroscience one, one course and you start learning about synaptic plasticity, that's when you get introduced to NMDA receptors. And the basic sort of cartoon idea here is, you know, if one neuron is talking to another neuron, there's some level of stuff happening in the second cell. But if a bunch of neurons simultaneously start talking to that same downstream neuron, you get this extra receptor that comes into the scene, it's the NMDA receptor. And that's directly tied with a bunch of stuff that happens inside the cell that's necessary to physically reshape the synapses of that cell. And so ketamine, you're saying was known already to block this receptor, and that that seems to be a key thing here for preventing the type of plasticity that you tend to see with drugs of addiction.

Christian Luscher 24:32

Absolutely. So the blockade of this NMDA receptor precluded the plasticity from being induced that's a technical term we use. And the way usually this plasticity is expressed is that the NMDA receptor triggers the insertion of the other glutamate receptor, which is the AMPA receptors, and that makes the synapse stronger. So you can measure and that's something we did in this project. The ratio of If the current flowing through AMPA receptors, and the one flowing through eminent NMDA receptors, and when that ratio goes up, this is a reflection of a strengthening of the synapse. And that did happen with cocaine, but not with ketamine.

Nick Jikomes 25:14

Not at all, or less, not at

Christian Luscher 25:17

all. So that was the thing. So at the point that we were sort of saying, well, maybe we should be challenging the system a little more. And so we developed a sort of injection protocols that would overcome the fast return to baseline by giving injection ever so often, we were able to accumulate the dopamine searches and make them longer artificially by you know, carefully, each time it goes down, you give another shot of, of ketamine. And that then gave us larger and longer dopamine searches that were comparable to the one with cocaine. And despite that challenge, we still had no plasticity whatsoever.

Nick Jikomes 25:57

I see. So even though you get the surge in dopamine, even though you can make that bigger by giving more doses of ketamine, one after the other, the fact that this drug is blocking the NMDA receptor is preventing that next step of plasticity. Yeah, exactly. And are you what kind of doses are you using here? Are they are they doses designed to be comparable to what people would use in a recreational setting?

Christian Luscher 26:20

Absolutely. So these are doses that are compared to the recreational and well below the anesthetic. So we made sure that when we give single doses, the animals would show a reaction as they also show with cocaine of a sort of moving a little bit more, we call this hyper local motion, but it was not sedative. At that stage, we were well below anesthetic concentrations.

Nick Jikomes 26:45

So an interesting question, I think that's just occurring to me is, so you're using a dose that's comparable to what a recreational user would use, which would have psychoactive effects. It's much lower than the dose that a doctor would use for anesthetic effects. What's interesting about ketamine in the realm of acting as an antidepressant, as my understanding is people are using low doses even lower than the ones that would give you psychoactive effects, or dissociative effects. Did you test the lower doses here and see what was going on? Because I could actually imagine, in principle, right, maybe if the dose is sufficiently low, you get some of this dopamine surge, but not so much NMDA receptor antagonism? And is there anything going on there at the low end of the dose, right, we

Christian Luscher 27:27

did try different concentrations, and we settled for one that was comparable to the acute responses we saw with with cocaine. So I don't believe that lower doses would be more dangerous. I don't think that would be the case, I think the system is imbalanced. And if you go lower, than there's virtually no dopamine surge, and for that reason, that mechanism may then prevail.

Nick Jikomes 27:53

And so what does this mean about thinking about the addiction liability of ketamine for humans, because on the one hand, your results are quite striking and clear. On the other hand, you know, anecdotally, at least, we do seem to see that some percentage of people do start habitually using ketamine after they start. So should we think of ketamine as non addictive or just weakly addictive? Or how do we think about that?

Christian Luscher 28:19

There is no guarantee it's not addictive. And for that reason, we actually carried out the third group of experiments where we tried to induce compulsion nevertheless. And that, of course, is something that was a tricky experiment, because you have to do many, many individuals in order to conclude that there is nothing but we did a reasonable number of animals and we did not find a single one that would become compulsive or really would be ready to even self administer if it is a little bit more complicated. That is if they have to press several times, and that they simply wouldn't do any more. So yes, we think in the animal model, with all its limitations, the indication is that the addiction liability is low. So how does that translate to the human? Obviously, it's something we now have to discuss with the expert on human addiction. And human imaging will be helpful and larger epidemiological studies. So what we provide here is sort of guidance through the neurobiological mechanism. But of course, this is not a guarantee that there's zero addiction. But I think it had we found the other way have we had we found all these changes that we typically see with addictive drugs, then it really would have been a red flag, and people would have to discuss again, whether it's a good idea to give ketamine to many people in the context of treating their depression. I think it's a it's a discussion of access to care who should get it? Because you could argue that The maybe some people of whom we know that they're vulnerable or they already have been addicted, they should have special scrutiny in terms of being treated with ketamine for addiction or for depression. Sorry.

Nick Jikomes 30:14

I see. And, you know, I know this wasn't the focus of your paper, you were looking at the addiction liability of ketamine and dissecting some of the mechanisms that were at play there. Do we know what mechanisms are at play for the rapid onset antidepressant effects that people have been observing? This is

Christian Luscher 30:31

also just an ongoing discussion. But I think there's very compelling evidence also from animal models, in particular, from the lab of Highland who and China, where she has been able to identify a part of the brain, the lateral habenula, as one of the prime targets of ketamine. And so what she has been able to do is to show that in these neurons that are upstream, actually of the ventral tegmental area, that there are NMDA mediated bursts in mouse models of depression. And ketamine, successfully suppresses these bursts these repetitive activity. And when you do so, then some of the symptoms that may reflect elements of depression in the animal model disappear. So I think that is a very compelling and very interesting observation. And the field sort of builds on that, to better understand how it works. But it goes to show that, as with many drugs, the locus, it acts in many locus is in the brain and in the VTA, it has something to do with addiction and the lateral habenula It's probably more the antidepressant effect. So this is this is a very common theme in all pharmacology, that the drug goes through the entire brain, but has very specific effects, depending on where it acts.

Nick Jikomes 32:04

I see. And so, you know, going back to your your results, you know, ketamine causes this transit, short term surge in dopamine, it doesn't cause the stuff that happens downstream of that, that other drugs of addiction cause. Is that very unusual, or are there other examples of drugs that have that property?

Christian Luscher 32:23

Now, to my knowledge, this is the first time we had this unique constellation of increasing dopamine, but then not engaging the subsequent cascades of plasticity that we know underpins the adaptive behavior in addiction. Now, it didn't set for us was also was the first time we saw such a drug that could do that.

Nick Jikomes 32:45

Yeah, interesting. Yeah, it was the first time I had heard of it. And it's, you know, it's a very convenient property for the drug to have. What are some of the questions that your lab is asking now? Or what are some of the big open questions in the realm of ketamine and how its operating in the brain?

Christian Luscher 33:04

Well, certainly, we would like to better understand the additional functions of ketamine such as depressive, so how to put together as sort of a unifying element, there are also questions as to additional targets in on top of the NMDA receptor. That is, is not so clear how this really works. So these are some of the questions that we have. But of course, for us, we probably going to go back a little bit more in the core questions of addiction. And what for us is a really basic question is to identify the neural signature of those individuals that eventually will go on and become addicted. So can we find in the brain something special, you know, transcriptome trend, transcriptional signature in some cells that would predict that some individuals become addicted. And I this is one of the questions and related also to ketamine and, and psycho dellux that we mentioned, there is an additional system that impinges on it that we haven't mentioned yet, which sort of modulates the way dopamine works in part and that's the serotonin system. And that is very interesting, because it is a system that is much more diffused projects. Basically everywhere in the brain has a large short number of receptors then dopamine receptors, and can change synapses as well. So maybe the same synapse that undergoes change because of dopamine, then also receives messages from serotonin to change in a different way. And we have in the past, we have 2021, we have had a first look at the interaction between dopamine and serotonin. And that actually is a really fascinating topic that we refer to develop in our lab,

Nick Jikomes 35:02

in terms of ketamine is pharmacology so antagonizes or blocks the NMDA receptor? Is it known to have other direct receptor interactions? Or is that an unknown?

Christian Luscher 35:13

No, there there, there's binding to other receptors. The question is only how strong as the spine and how how pharmacologically relevant it is, as I mentioned, people have claimed that there is binding to the D two receptor. There are some other receptors that it binds to also, but it there's no unifying agreement on how important it is for very specific functions.

Nick Jikomes 35:38

Interesting. And so what's your expectation with respect to how ketamine will continue to be used as a therapeutic in humans? Do you think it's likely that we'll see larger scale clinical trials, replicating some of the the antidepressant effects we've seen so far? Do you think there any major risks to continuing down this path? What do you think about the human side?

Christian Luscher 35:58

So my reading from the outside of that field, as I'm not doing active research myself is that yes, I mean, it's definitely been a game changer in the terms that for the first time we had a drug that could act immediately. The typical antidepressants such as the reuptake inhibitors of serotonin, they only act a few weeks after you started the treatment. And that has always been a very, very serious limitation of the of the effects. And so, so So to have this rapid one is really it was a game changer. But people now realize that unfortunately, these effects are not long lasting at that many people who receive ketamine as antidepressant respond initially very well. But then the effects somehow wears off, even if you repeat the dose. And so I think that is going to be one of the big challenges in the field. And again, knowing the underlying neural mechanism may help you to overcome this desensitization, if you will. So I think that's going to be one of the big questions that people will ask.

Nick Jikomes 37:11

Interesting, well, Christian, is there anything else you want to leave people with in terms of your recent results, or this field generally, when it comes to ketamine for depression, or the addiction liability of a drug like this? Well,

Christian Luscher 37:25

I guess one element that I find really interesting, but somewhat also puzzling, is that when you look at the vulnerability to drug addiction, in animal models, it is interesting that we can reproduce these two groups that we saw, so seeing the human, so it's really not a big variance, where we then take the top and the bottom of that distribution, but with the combination of giving a drug and having a negative consequence, we have really two groups emerging. And as I said, for cocaine, it's roughly 20%. And this is also true for mice. So the, you know, maybe it's 18% or so, but it's roughly the same proportions. And I find that very difficult to understand. Because if it's genes that control your vulnerability, the mice that we use are genetically homogeneous, they're inbred, and they are a special line, and they are virtually identical. Humans, on the other hand, obviously, are genetically very diverse. So how is it even possible that this leads to the same proportion. And so one idea that we had and others also is that it may actually not be the genes that determine your vulnerability, but it may be epigenetic mechanism, regulating the expression of genes in specific cells. And that is something I find really interesting and something we're actively pursuing in the lab, we would like to understand how life experience such as PDA, you know, strong stressor, or, or something also very beautiful, can have an effect on the expression of genes in some cells and therefore, reorganized circuits in a way that in the end, someone is resilient or vulnerable to drug addiction, and that may actually have a shared commonality with the vulnerability to depression and other psychiatric diseases. So I think that is an exciting avenue of research, knowing that from circuit neuroscience where we should look and so we go look now and we can see, okay, in those cells, there is before the individual even is exposed to the first drug dose, there is something going on that makes this person vulnerable to addiction and By extension, possibly also to depression.

Nick Jikomes 40:02

Interesting. Yeah, no, it's a it's an interesting question. What you're saying is, you know, roughly 20% of people who use cocaine develop compulsive drug seeking behavior. That's also true in mice, roughly 20% will develop that naturally, one might think, well, maybe 20% of people have a mutation and a dopamine receptor gene and that predisposes them or something. But what you're saying is, that can't be true, because it's true of the human population, which is not inbred, and it's genetically diverse. But it's also true in these mice, but they're genetically basically identical.

Christian Luscher 40:34

Yeah, and the active search for all these prime candidates have dopamine receptors or, or restore or the the molecule that binds cocaine, and so have not yielded differences between people who are addicts and people are not. So the very first attempt was, when people realize that among the three opioid receptors, the mu receptor that drives that positive reinforcement that eventually may lead to addiction, and someone takes heroin, for example. And now that they have looked very carefully, the opioid receptor in heroin addicts is no different from an opiate receptor in a normal person who and the person who is not addicted. Yeah,

Nick Jikomes 41:16

how do you even start to think about how you would experimentally studied that? Would you? Very carefully try and control the early life history of mice, and you know, subject some of them to certain stressors or prevent certain natural stressors, and other ones and see if that is causing them to develop this propensity to addiction?

Christian Luscher 41:37

Yes. So you could, for example, also look something that mice do they have a social hierarchy within a letter, and you see whether there is a correlation between the rank in the literature and the risk, then you can do select animals for some individual traits, such as impulsivity. So we made, for example, the observation that animals that in operant behavior, and cannot wait to press the lever, even if there is a timeout, which can could be somehow interpreted as a reflection of impulsivity, that these mice are more likely to go on and become compulsive. So yes, you can select for some behavioral traits. And you can then also challenge the mice, for example, by separating them a little earlier from their mother, which is a very strong stressor for them and see whether that has an impact on gene expression or epigenetic mechanism. And eventually drug addiction.

Nick Jikomes 42:35

Yeah, it's fascinating stuff. And, you know, it could tie into your work that brings serotonin into the picture, because my understanding is a lot of the serotonin circuits are at least partly involved in things like an animal's knowledge and perception of its own sort of social status and where it falls in these hierarchies.

Christian Luscher 42:51

Absolutely. I mean, we're all into now serotonin is I think it's really exciting. And again, for two reasons, because these genetically encoded sensor are also available now for serotonin. So we don't only have the D light, we also have the ES light. And now we can monitor serotonin when an animal moves around and see when does it think when does it change. So this is this is one of the thing and the other thing is that we know that the serotonin system is the target of psychedelics. So the five HTT to a receptor is the is the primary target of psychedelics. And there have been again, anecdotal reports that some people find it easier to quit drugs when they have taken psilocybin, for example. But that, of course, is a little bit anecdotal. And it would be extremely helpful to the field if there was some mechanistic insight. And so these are some of the questions were were asking and we're actively pursuing in the lab.

Nick Jikomes 43:52

Well, Dr. Christian Lucia, fascinating stuff as always, and it sounds like before too long, I'll probably send you another email to come back and tell me about some some real pleasure

Christian Luscher 44:03

thank you so much.


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