Friday , October six , Episode four . How are you doing ? 11 00:00:11,778 --> 00:00:00,-01 Dr. Stout: Good , good . Hi , this is Dr. Stout . Continuing where we left off , but I'm taking a bit of a tangent , so we were talking about the growth of the brain and imagination and abstract thought and language and art and all of that sort of interconnected aspects of human evolution .
And I wanted to go into a little bit of my own research , which is on dopamine , and I thought this would be interesting because dopamine is sort of the reason we do things . It it's the goal in our life . It's it's the it's the reward for what we do . And I want to talk a little bit my own theories on dopamine , which are different from what a lot of the established work on dopamine would claim . So I have I have some different different thoughts on on the subject .
So I was interested in looking at dopamine , mostly because I have very little funding and I wanted to have something that I could just try out . And dopamine is relatively inexpensive and I had a bunch of crayfish in my lab , so I wanted to see what would happen if I gave dopamine to crayfish . This isn't something that I was a , you know , major , major grant or anything . It was just sort of a fishing expedition in that I was just trying something out to see what would happen .
And all the literature agreed . It all said the same thing , that dopamine is a stimulant . Dopamine is the sort of active ingredient in things like cocaine or nicotine or caffeine or basically all methamphetamine . All all the stimulants are , in everyone's opinion , dopamine . And so they are dopamine . Well , so here's the thing . Dopamine cannot be given directly to a mammal because we have a brain blood barrier . If you take dopamine , it doesn't get to your brain .
And so what we do to get that good feeling from dopamine , the reward is we take dopaminergic drugs , drugs that generate dopamine in the brain . And so it's already in the brain when it's generating the dopamine . And that makes us feel good . And those that's what makes us addicted to these drugs . So all . 380 00:02:18,948 --> 00:00:00,-01 Eric: Of those drugs that you mentioned caused us to to generate the dopamine . 394 00:02:24,948 --> 00:00:00,-01 Dr. Stout: In some
way 398 00:00:00,-01 --> 00:02:25,998 . In 399 00:00:00,-01 --> 00:00:00,-01 some way . They sometimes they do it in different ways . But yes , we we end up with more dopamine in the brain and we feel great . An so I thought that I would be giving dopamine to my crayfish . And it'll be interesting because as far as I could tell , no one had ever done this . They done it with rats , they done with a bunch of different things , but they hadn't tried crayfish .
And so it was just sort of a fishing expedition , you know , low level science . Let's try something . And so I gave the dopamine to the crayfish , and the crayfish slowed down everything , said they should speed up , but the crayfish slowed down . So I said , okay , let's try that again . Clearly , I'm not doing this right . And I tried it again and I tried it again . I tried a different species of crayfish , and still , every time I gave it to them , they , they , they moved more slowly .
So I was just I was just looking at them walking over a grid after I'd done some things to get them to walk over a grade . It's really actually hard to get crayfish to walk around . They either want to hide or they want to run the whole time with no , no differences . So I had to get them calm , but not too calm . But anyway , I figured out how to do all that . Then I gave them the dopamine and they slowed down and I could compare it without the dopamine .
They were faster and so , you know , the first stuff I started doing was , you know what ? What make them move around faster . So I just tried some very simple things . I know crayfish like food . So I took the water that filtered through some food and I gave it to the crayfish , and that definitely made them move around faster . But again , even in the present when I added dopamine , even the present presence of food filtrate , they'd slow down again .
So then I wanted a lot more data on the crayfish . I just couldn't get enough crayfish to get really good statistics . So I started working with much smaller shrimp that breed much faster called cherry shrimp , and I was able to get a ton of data . Same results every time I gave it to them , they slowed down . So why would this be ? I had to come up with a sort of new hypothesis . I thought I was dealing with a stimulant and I was clearly not dealing with a stimulant .
It's possible that crayfish are just unlike all other organisms , but that didn't seem true . Or all crustaceans are unlike all other organisms that didn't seem likely . So I wanted to just sort of think about this for a little bit . And I realized that because there was no brain blood barrier , all of these stimulants were being given to organisms as a collection of different I different drugs essentially that could have different effects .
And one of the things that all of these stimulants also have in common is epinephrine . S basically adrenaline . And I do not claim that adrenaline is not a stimulant . It's something I'm going to be working with soon . So that's sort of a direction I'm going . But I had to figure out what was happening . Why would people think of something as a stimulant that was really not a stimulant ? Was was the opposite of that was is in some way inhibitory .
And I realized that what people had done is they had mistook the nature of a reward and we think of a reward as a stimulant . A reward is what makes you want to do something . But if you think about the donkey chasing a carrot tied to a stick , if you actually give the carrot to the donkey that the donkey stops chasing that carrot , it's sort of I told my students , it's like a grade . You're trying for the grade . The A is your reward .
But if I give you the A at the beginning of the class , you all slow down . And so people have been thinking about rewards in the wrong way . They've been thinking about rewards as something that causes you to do something . And then a lot of the research out there , I'm not saying any of the researchers had done anything wrong . All of their research was correct , but I think they've been misinterpreting it .
So the classic stuff that's done on , on on rats , they would give dopaminergic drugs . They would see them become stimulated and then they would block that . They would use Haloperidol , Haldol , the antipsychotic drug . It blocks all dopamine receptors and they would watch the rats become catatonic and the rats would just lie there flat . And so in my model , this was because they no longer had anything to strive for , right ?
Ther was nothing in their life worth doing , anything not even standing up because they no longer had the option of getting an A right . So you tell the kids , none of you are going to pass this class no matter what you do . They're also not going to do any work right . So what happens if I then give them a little bit of that thing ? They want just a tiny , tiny bit . The rat's going to get up or at least do something .
So what these researchers did back in the late eighties was they put a little bit of cocaine in some water or a little bit of sugar in some water , put it directly into the rat's mouth and watched the rat bother to suck it down . So there was a tiny , tiny bit of a reward . And they said this means that the reward is not the same as the thing that makes them want to suck .
The reward is actually a stimulus , and it's a measure of so the dopamine is a stimulus and it's what they call a salience measure . It's a measure of the value of the thing you're going to get at some later date . And so dopamine is is the thing that tells you you have a carrot in front of you , but is not itself the carrot . And to me , this seemed a rather magical .
Yeah it's it reminded me of of sort of the Ptolemaic universe where they start adding epicycles to things and they're coming up with , you know , William of Ockham , Occam's Razor . He said that you shouldn't multiply entities . What he was talking about was angels . How many angels do you need between you and God ? You need to keep multiplying angels so you can talk to God . Probably not . So we shouldn't multiply entities .
This seemed like they were multiplying entities that they were going against Occam's Razor . Now sometimes outcomes are wrong . Sometimes the complex explanation is true , especially in things like , you know , neuroscience , where things are very , very complicated . Already the brain has many , many feedback loops all acting on each other . It's very difficult to tease apart cause and effect .
One reason I really like working with crustaceans , crayfish , everything is very direct , no brain blood barrier . I can put the dopamine in and they respond to it instantly . So the the the model out there was that dopamine was a measure of salience . It was stimulatory . The more salience something had , the more you would want it . So the more dopamine you encountered in relation to it , the more you would want that thing . But the
thing . 1671 00:08:47,838 --> 00:00:00,-01 Eric: Was always going to be a future thing . It was not . 1683 00:08:51,408 --> 00:00:00,-01 Dr. Stout: Or it was something else . It wasn't dopamine , and I haven't quite figured out what they're trying to say . It was . It was the cocaine or the sugar or the thing they put in the mouth that made the rat happy .
But it wasn't the dopamine itself , because their reasoning was if you blocked all dopamine with Haloperidol and the rat is lying there flat on the ground , it wouldn't look happy when you put cocaine in its mouth . I'm reasoning that it would look happy when it put cocaine . It's not because suddenly it's getting a little bit of that dopamine it wanted .
And under those circumstances , dopamine will be slightly stimulatory in that you're finally getting that thing you thought you couldn't get before . Similar experiment in fruit flies . So something that actually doesn't have a brain blood barrier is a an invertebrate , you know , not exactly a crustacean , but very closely another arthropod , something with a jointed exoskeleton . And what they did is they made fruit flies that didn't express dopamine .
Now , if you remove all dopamine , the thing's dead . So it had a tiny bit , but it was a what they called a dopamine knockout fruit fly . So it wasn't expressing any dopamine . And these these fruit flies weren't flying around doing nothing like the rats were . They put a tiny bit of sugar water with some dopamine under the fruit flies and the fruit flies started drinking the sugar water with the dopamine in it .
And so they said this confirmed what they'd seen in the rats that they were the fruit flies were acting exactly as the rats were . Dopamine was not a reward . Dopamine was something that measured . The reason you would bother sucking was because you were now getting some dopamine . And so dopamine was a stimulant and it was all just a measure of reward . I find all of this confusing and too much . Okay . A reward is the measure of reward .
If I want to know how much money I'm going to get , it's the pile of money , right ? The A is the measure of the reward , but it is not separate from the thing you're trying for . The actual grade is the thing you're trying to get . Dopamine is the actual reward . You measure the reward by how much dopamine you get . Now , there's some interesting things . You can get more dopamine when you get an unexpected thing that's happening to you .
So if you meet someone beautiful who you really , really like for the first time , your brain is going to release a bunch of dopamine . You meet them a second time , your brain's going to release a slightly less dopamine , but you're going to want to meet them that second time because of that first time when you got that reward . So dopamine tells you what to do . It gives you a little bit of an extra sort of extra credit if you get something unexpected
happening 2184 00:00:00,-01 --> 00:11:19,908 . But 2185 00:00:00,-01 --> 00:00:00,-01 it's the measure of the things you want to do and our brain can't tell the difference . So it'll give us dopamine for almost anything . Our primate ancestors would have seen fruit ripening on a tree . That fruit would have turned orange or red signaling . Let's go get that fruit that those are those are colors that will stimulate some dopamine . So we're often stimulated by flashing lights and bright colors .
This is what all the video games do to give us rewards and make us want to come back and do it . This is why we do things that are addictive . Give us dopamine . And part of the reason why many things online can be addictive is the the fast editing , the flashing lights , the bright colors . All of these things stimulate our brain , give us rewards and make us want to come back . I'm not arguing with any part of that particular model .
I'm just saying that I think they're thinking about these things wrong , that dopamine is exactly what we've always thought it was . It's a reward and you give something the reward , they slow down , but you prevent all rewards and they also slow down and you give a little bit of a reward back again and things might start moving again because now they have an incentive . They know what they're going to try for . So again , it's the carrot on the end of the stick .
You give them the carrot , they don't they don't chase it anymore . But if there's no carrot there , they also don't chase it . Right . So dopamine is the the actual physical goal . And all of my research seemed to to to to go with that really well , I was able to isolate at least one of the causes for stimulation and crayfish . Right . I started off with looking at food , filtrate . I then found out it's the amino acid I glutamate that really makes them run around . And I this is glutamate .
It's interesting . It's almost the only thing that does go through a brain blood barrier is the number one stimulatory neurotransmitter in the brain . And it's definitely the signal for food in in crayfish . And it's also the signal for protein in our in our in our tastes . Right . So we only have a few tastes , you know , salty , savory . 2579 00:13:28,638 --> 00:00:00,-01 Eric: It passes through the blood . 2585 00:13:31,188 --> 00:00:00,-01 Dr. Stout: Brain blood barrier . Yeah .
So , so if you eat glutamate , it will go into your brain and is having an effect as a neurotransmitter . I had not really realized this until I started doing this research . And so glutamate for free for the crayfish or the shrimp is a signal that they there's there's food somewhere in the water . And so they run around . I give them dopamine , they slow down again . I block that dopamine with haloperidol , they speed back up again .
I suspect if I tried longer term studies , if I gave them Haloperidol for an entire day , they wouldn't speed back up again , right ? They would just stay slowed down because now they have no reward . I think that part of what I'm doing is I'm working with undergraduates . No one has any patients . We have no funding . So I do 20 minute experiments . And so in those 20 minutes , if I blocked dopamine , all the shrimp don't realize they've lost the carrot .
They just think that the carrot is hidden somewhere . So they have to keep running around looking for it . I think if I did it for 24 hours , they would they would run out of energy over time , you know ? And so these are some directions I want to go with my future research . I particularly want to look at caffeine . Caffeine is a nice legal drug that I can work with . And I've actually found research out there that says caffeine is a stimulant in shrimp . And I'm like , aha !
And they said , it's a stimulant in shrimp because of dopamine . I said , You're wrong . So I can I can I can demonstrate this because I can block I can block epinephrine , I can I can use beta blockers and alpha blockers to block all the receptors for the adrenaline related drugs , the neuro epinephrine , all of these things . I can block dopamine and I can give both these things . So I can give caffeine on its own . I can give caffeine with dopamine blocked .
I can give caffeine with epinephrine blocked , and I can give these things separately so I can show that dopamine is not a stimulant on its own . Epinephrine is a stimulant on its own . And then I can show caffeine working with and without these things . So that's sort of my future direction . I'm planning that next semester . I'm very confident in what I will find , because I did , you know , a couple hundred shrimp and many , many crayfish looking at them with dopamine and haloperidol .
An definitely it is it is inhibitory . And I also have some other hints on the model using dopamine as a measure of , as they say , salience . I call it teen salience . Teen Salience can't explain all of the available observational data out there . It certainly works in their rat models because of how I described it . Right ? You give them Haloperidol the flat , you put some cocaine in their mouth , I bother to bother to suck it and look happy about it .
That's like their whole model is based on . If you think about ADHD , ADHD is classified as a dopamine deficiency because of my work with glutamate , I wonder if it's more a glutamate surfeit , right ? So it might be neurotransmitter is activating the brain too much rather than I not having enough dopamine . But the model works for me , right ? If you have more dopamine , you are more focused because you're not seeking something all the time . You're not looking for that carrot .
If you have a little bit of that carrot , you're going to calm down a little bit . And so that would actually align with the ADHD model people who have attention deficit to deficit disorder are always seeking rewards . They have a tendency to seek dopamine providing drugs . They have a tendency to do thrill seeking . They often make a lot of bad decisions because they're always looking for that next reward . And so the model is that they don't have enough dopamine .
I'm not positive this this model is entirely right . I think it might be too much glutamate , but that's a separate issue . But certainly more dopamine would help , right ? They would they would calm down . So how do we treat ADHD ? We give people essentially amphetamines . We give amphetamines to people who are hyperactive to calm them down . How does this make any sense ? It makes sense because the dopamine calms them down .
If they now had a reward , the epinephrine portion is still stimulating . If you are if you have ADHD and you are taking a an amphetamine , you can have a hard time eating because that's what stimulants do . Your heart is going to race quickly because that's what stimulants do , particularly for epinephrine . You're going to have a hard time sleeping because that's what stimulants do . It's not that the amphetamine has suddenly magically for you not being a stimulant .
You as as someone with ADHD certainly are being stimuli aided by amphetamines . 3429 00:18:12,618 --> 00:00:00,-01 Eric: So according to your theory , then what would be a better treatment ? 3442 00:18:17,118 --> 00:00:00,-01 Dr. Stout: That would be hard . Something that that that that slows down the amount of glutamate in the brain providing dopamine in some way separate from the stimulatory effects of amphetamines would be another possibility .
You know , amphetamines are not the only way to get I don't mean to the brain , it's just that in general , dopamine is , you know , found in stimulants . But there are a few other things . Marijuana , for example , is slightly less stimulatory but does provide dopamine . It just has its own issues , memory , etc. But too much dopamine actually does have problems . Okay . So this is why , for example , methamphetamine use is often associated with various kinds of psychosis .
Dopamine leads to schizophrenia . Schizophrenics have way too much dopamine in their brain . And so you treat schizophrenics with something like Haldol , haloperidol , classic , you know , One Flew Over the Cuckoo's Nest . People don't stand there , don't say anything , don't move , because they've been given this dopamine blocking thing and they have no no joy in their life . We've gotten a little bit better with this .
There are a few selective antipsychotics that block some dopamine somewhere in the brain , but not other places . So it's been a little bit adjusted . B these are these are ways that we've figured out to lower agitation in in in , you know , patient patients who are in , you know , mental distress . Haloperidol will work that way because it's often too much dopamine . So these are what we see often with things like amphetamines and and with with cannabis as well .
Typically the side effects include paranoia . This is a side effect that is caused by too much dopamine . So these these drugs have what you would expect in terms of , you know , classic effects , as predicted , They work as rewards . They they they make us want them more . And and the model fits for most of it . Right . So that dopamine is in fact a measure of a reward . But that reward is the dopamine .
So their model kind of works for a lot of situations , but I don't think it explains ADHD people . Right . It doesn't explain why it would make you focus more when you're given an amphetamine . It doesn't it doesn't explain the entire model . Right . Why why would hyperactivity be defined as a dopamine deficiency ? If we think dopamine causes activity ? Right . Hyperactivity would be more of that thing .
What happens when you have too much dopamine is you end up with with with psychosis , which is something else entirely . So not enough dopamine . We run around looking for things too much dopamine . We become paranoid . But if we can nail it just right , then we're happy . And so this is this is this is you know , I'm in agreement with the original model of dopamine . The dopamine is a reward . It's the reason we want to do things .
And our brain can't tell the difference between one thing of dopamine and another . Ri ? So if we meet the person we love , we get dopamine . But if we want to invite someone on a date , on a date , you take them out to dinner . The person can't tell the difference between the dopamine provided by the dinner and the dopamine provided by the sparkling conversation . Right ? So our brain just eats all this stuff up , right ?
We were evolved to be attracted to bright colors and things that would give us food as as primates and monkeys in the trees . So we give each other a bunch of flowers when we go on a date . The bright colors of the flowers provide dopamine to the brain , signal those things that are attracted to these colors . And again , you can't tell the difference , but so you now like the person who gave you the flowers because the flowers gave you a reward .
And our brain can't tell the difference between the person and the flowers . Same thing with perfume . So , you know , I was just talking to my students about this flower is have a scent to attract a pollinator . Those scents were originally derived from I insect sex pheromones , and the flowers didn't want to just have those particular sex pheromones , but they wanted to attract males and butterflies .
So they modified slightly moth and butterfly insect sex pheromones and made a perfume out of it to attract the moth and butterflies to come as pollinators . We then take that same thing that's been evolved co-evolved between animals and plants to attract animals . And we put that perfume on ourselves . When someone comes and smells it , they get a little dopamine reward and they say , Oh , I really like you .
And what they really like is the scent of scent of something tasty or the floral smell that is originally designed as a as a plant manipulation to cause a dopamine response in a in a moth . And so all across the the the the the animal kingdom , dopamine is is is used as as as incentives , as ways to make things happen . Plants are constantly manipulating these things . They found small amounts of caffeine in nectar , again , rewarding things to come back . Dopamine is associated with memory .
They think that when bees find a little bit of caffeine in the nectar , they'll remember that plant over other plants because now they've been given a little bit more of the reward . I think there may well be some interactions with glucose , but that's complicated . So some things are themselves attractive . Like do glucose is the number one energy molecule for all cells in all things .
So I think glucose maybe is even more primary to as , as , as , as a as a thing we want than even dopamine is . But again , dopamine would be the measure of how good that glucose was . Right . So if you get a piece of candy immediately , your brain is is is is releasing some dopamine and saying , do that again . That was great . Right ? And then you'll want that even more if the candy is brightly colored . Right . So all all of these things are related .
We were always seeking these these various rewards . We we're using them in our lives all the time . You know , the fashion industry talks about dopamine colors . They're talking about red and yellow and orange , the things that would signal a ripe fruit to a primate . There are these these are our co-evolved heritage of rewards that plants have manipulated into our brains . If we didn't if we had not learned how to respond to the bright colors of ripe fruit , we would have starved .
So we responded to those bright fruit fruits The plants wanted us to spread their seeds , right ? They wanted us to eat the orange and poop out the orange seeds so the plants co-evolved with us . They made better colors when we ate those things , they got they did better because they spread their seeds . If we didn't see those colors and we didn't get a reward from it , we didn't eat the food . And so we didn't didn't survive .
So this was a coevolution of of a system of rewards that had already pre-existed . And that's why that's why I think that it legitimate to be working with crayfish and crustaceans in general , because I think that the dopamine is so basic to the way all life has evolved that I looking at an entirely nother branch of the animal kingdom other than other than mammals , I think is useful .
And I think what I have done is I've come up with a simpler model that explains how dopamine works , that is is is better than the existing ones . And it explains more of of the observed , you know , the universe around us . Fascinating . Well , thank you so much . All right . So that's my research . I will talk again next week . 4766 00:26:08,198 --> 00:00:00,-01 Eric: One bit of your research . 4772 00:26:10,598 --> 00:00:00,-01 Dr. Stout: Yes .
Well , that's that's what I'm focusing on at this particular moment in time . 4787 00:26:14,498 --> 00:00:00,-01 Eric: All right . Very good . Well , thank you very much . We'll see you next time . 4802 00:26:18,698 --> 00:00:00,-01 Dr. Stout: Excellent . Thank you .