This week we have Dr. Emily Witt, who discusses a behavioral technique called Self-administration and how do we use this technique to understand the abuse liability of a molecule. Thank you for joining us, and I hope you keep listening.
This week we have Dr. Emily Witt, who discusses a behavioral technique called Self-administration and how do we use this technique to understand the abuse liability of a molecule. Thank you for joining us, and I hope you keep listening.
Hello, everyone to another episode of nerd RX podcast and I'm your host Barkha. Today we are going to talk about a behavioral technique called self administration. And to talk more about that, we have Dr. Emily Britt. welcome Emily to the show. Thank you. And guys, Emily also has a podcast, please make sure to check that out. It's called cover to cut. And, Emily, thank you so much for giving us your time. So before we jump into the topic, why don't you introduce yourself so we know more about you?
Dr. Emily Witt:
Sure. Sounds good. Thank you so much for having me. So, again, my name is Emily wift. I am originally from Tennessee. So I did my university undergraduate degree at East Tennessee State University. And I got a bachelor's in psychology with a focus in behavioral neuroscience and a minor in biology. And then I went on to attend the University of North Carolina in Chapel Hill for grad school, where I worked under Dr. Catherine rice. Reisner Excuse me. And now I'm doing a postdoc at Dalhousie University in Nova Scotia.
Dr. Barkha Yadav-Samudrala:
Wow, that has been a quite a change from US to Canada. How's the weather treating you by the way? It's amazing. I love it. I've always enjoyed cooler temperatures. Oh, wow. It's been a nice change. mild summers are amazing. Oh, great. So self administration is the topic you chose for today's episode. So my first question would be what is self administration? And what got you interested in it?
Dr. Emily Witt:
Yeah, so self administration is a animal model. That is based on the principles of operant conditioning, which is essentially an animal's performing a response. And in after it does the response, it gets a reward. And the self administration model that I am most familiar with is lever pressing. So it's an automated box entirely with levers in it, and the animal goes in and presses a lever, and they can get a reward, which can be anything from delivery of food pellets, sucrose, or sometimes intravenous injections. And what got me interested in self administration was just kind of exposure to it in the first lab that I ever volunteered with at ETSU. In Tennessee, they were doing self administration models with nicotine, caffeine and alcohol, not all at the same time, but in different models. So that's kind of what got me interested in it.
Barkha Yadav-Samudrala:
My so self administration, I think, is mostly required to test the abuse liability of a drug, right? Yeah.
Dr. Emily Witt:
Yes. So it's a way to test animals motivation, because you can change the parameters for how many lever presses they have to press in order to get a reward. And for that you can monitor their motivation level is and how many times are they willing to press the lever for this substance versus this substance? And then can we test pharmacological compounds, which could reduce their motivation to seek those items? Yeah.
Dr. Barkha Yadav-Samudrala:
Okay. And how would you describe the experimental setup is like, how would you start? And how would you finish your experiment?
Dr. Emily Witt:
Sure, the first thing is definitely deciding what you want your experimental parameters to be isn't, you know, how do you want your reward to be delivered and what kind of ratio you want it to be delivered on. So how many responses equal, what reward, and then like timeouts in between the response and the reward delivery, and all that is written into computer programs, because it's an entirely automated process where you write a program, that would be step one, to figure out all the different parameters and how long the sessions are? Just things like that. And then you would need to, we did surgeries on our animals, because we had jugular catheters for the delivery of the drug reward. So that would be step two, is if you're going to do that it's an entire process to learn the surgical procedures. But I would say those are the two largest hurdles. The next bit of self administration is really just automated day to day you take your animal, you put it in the box and you let it run entirely automated and take them out. And then at the end, you can measure either just the behavior or you can look at changes in neurological things as well.
Barkha Yadav-Samudrala:
Okay, and so you worked with mice or rats?
Dr. Emily Witt:
Rats, yes.
Barkha Yadav-Samudrala:
So, is there a
Dr. Emily Witt:
A training period like you have to train the animal. Yeah, so we do a training session. And in that situation, they press the lever for food pellets. But there's also a food pellet that is dropped every, I think, one or two minutes, as well. And that's just how they learn to press a lever for food. Yeah. And does it take like, a long time to train them? No, just about one session, around six hours, and most of them get it less than six hours. I know. I remember in doing training with mice, is that correct? Yes. Yeah. And taking a long time. Rats, thankfully are much more intelligent. The rats are definitely more intelligent.
Dr. Barkha Yadav-Samudrala:
Yes, Ian who will also feature on this podcast? I think he's going to talk about fear conditioning. And I think that is he's going to talk about all his frustrations in training mice, Georgia that episode, because I remember talking in the lab meetings, and he would be like these mouths, like, he would take like months and months to just train them.
Dr. Emily Witt:
Yeah, this is like a six hour session, and most of them can get it within two hours, every once in a while, you may have to run an animal twice. Usually it's fine.
Dr. Barkha Yadav-Samudrala:
Okay, and how large is the group of animals to run? Like, what is your n? So we're in breed, usually, we're doing like you want 10 per group is usually a good number. But on average in Dr. Reiser's lab, we were running 16 or 24 at a time, but group
Dr. Emily Witt:
just in total for the okay. Yeah, so we didn't expect like 12 Yeah, cuz, you we lost a few due to patency. There always seems to be one. So it's better to have 12 per group, and maybe lose one or two. So.
Dr. Barkha Yadav-Samudrala:
Okay. Okay. So are there any alternative techniques, you could use other than self administration to assess the same things?
Dr. Emily Witt:
Not exactly motivation, there is a way to measure preference. So people will use conditioned place preference, which essentially, you have a three chambered like rectangle, I guess. And you inject the animal animal with whatever compound you're interested in and put it in one side. And then the next day, you would inject it with saline and put it in the other side. And you continue to do that for a few days. And then you put them in and measure how much time they spend in either chamber. And if they prefer, like the substance you're interested in, they will go to wherever they received it. But that really doesn't tell you anything about motivation, which is really key in self administration with lever pressing. Yeah.
Dr. Barkha Yadav-Samudrala:
So self administration takes precedent over place preference in terms of motivation, we can even Yes, assess the motivation. Okay. And what would you say is the in this entire process? What is the step that requires a lot of troubleshooting, or is the most difficult to deal with?
Dr. Emily Witt:
Probably surgeries, if you're going to be doing surgeries, that is, I think the biggest learning curve other than writing programs, a lot of programs are available online. So that's not as big of a hump to get over. And then just the mechanical things that can go wrong in the boxes, I think can be a hurdle. But other than that, probably just the surgeries and then writing programs maybe.
Dr. Barkha Yadav-Samudrala:
Okay, and so for example, you have these 20 animals, and you have already performed self administration experiment, and you used a drug A for example, could you use the same animals for something else or? No?
Dr. Emily Witt:
Probably not. It would depend on what you wanted to look at. Yeah, but probably not. Okay. Yeah. Depends on what the drug is and what you're interested in looking at, like how separate they would be if you have an example.
Dr. Barkha Yadav-Samudrala:
For example, cocaine. And for pain, fentanyl,
Dr. Emily Witt:
I wouldn't use the same sales from Yeah, I would do a different cohort unless your question was how cocaine self administration affected fentanyl
Dr. Barkha Yadav-Samudrala:
fentanyl? Okay,
Dr. Emily Witt:
I think we did do a study where we looked at it's just a pilot with a few animals looking at adolescent alcohol intake, where they did give OSH they were adolescents and then we took the animals when they were adults and did cocaine self administration. Yeah, something like that would be an interesting question.
Dr. Barkha Yadav-Samudrala:
Yeah. Okay. Yeah, animal work is always tricky.
Dr. Emily Witt:
Yes. It's so tricky. Yeah.
Dr. Barkha Yadav-Samudrala:
And I think the most time consuming experiments to lose,
Dr. Emily Witt:
I agree. Yeah.
Dr. Barkha Yadav-Samudrala:
So would you say self administration is something that a complete novice could learn easily, or there is a learning curve to it?
Dr. Emily Witt:
I think you could learn it pretty easily. So the like, the materials you need, like, the boxes, and the programming, like the main company that provides those is pretty good with their manuals. Like I learned to program going through their manual, like, self taught, like going through how to program things that way. Yeah, I think it's takes time, but I think it could be self taught entirely. Yeah.
Dr. Barkha Yadav-Samudrala:
Okay. And I think it is probably not surgeries. Yeah, I think your surgery is the one. So I always thought about this question. And now you mentioned that you perform surgeries. So it's that lever where they have the drug? Is it connected to the rat to get the truck?
Dr. Emily Witt:
So yeah, there's tubing. So essentially, it runs to their jugular. And then a tubing runs out their back and there's a port that comes out their back, and that's what we connect inside the box. And then there's a syringe that's hooked up on a motor, which you program to deliver a certain amount or a certain amount of time when they press the lever.
Dr. Barkha Yadav-Samudrala:
Okay, okay, that makes more sense, because I would always think, self administration, how would they get the drugs.
Dr. Emily Witt:
But there's so many different ways to deliver things like there's a, like a dipper, that is essentially, if you can imagine kind of like a seesaw, you press a lever, and it like brings up a certain amount of liquid. And then there's like a pellet dispenser that you can have to drop like sucrose or food pellets.
Dr. Barkha Yadav-Samudrala:
Yeah, I think the intravenous is a little time consuming. Like pellets. I would assume it's easy. It's just dropping
Dr. Emily Witt:
much easier. Yeah. If you're not doing surgery, you can do self administration much quicker.
Dr. Barkha Yadav-Samudrala:
Yeah. But then it also depends on what drug you're using. Right?
Dr. Emily Witt:
Certain drug requires a whole. Yeah. Which I Yeah. But yeah,
Dr. Barkha Yadav-Samudrala:
that would be oral, but something like cocaine would be intravenous.
Dr. Emily Witt:
Yeah. Yep. Sir. jugular catheters. Yeah.
Dr. Barkha Yadav-Samudrala:
Okay, so let's talk about the advantages and disadvantages of self administration.
Dr. Emily Witt:
Sure. So I think the advantages are really kind of the variability in the information you can get related to motivation. And the number of just models you can run, just based on how you're changing what is required to get a reward. I think that's the main advantage is that if you're running a progressive ratio, you can say that this animal is more or less motivated for this particular compound. Disadvantages, I think the startup cost is large. I'm not sure how much the boxes cost, but I know they're expensive. Yeah. And then surgery, if you're doing surgery, I think is one of those things of a disadvantage maybe.
Dr. Barkha Yadav-Samudrala:
Yeah, that was my next question about the costs involved in running this. I
Dr. Emily Witt:
think that is the biggest thing is the boxes, because they're all automated, because you likely need a large number if you want to run a lot of animals quickly. I think that is the biggest hurdle. Yeah.
Dr. Barkha Yadav-Samudrala:
Okay. And even maintaining the animals is added costs.
Dr. Emily Witt:
Yes, yeah. And then if something breaks in the box, like that's an added cost, and yeah.
Dr. Barkha Yadav-Samudrala:
Did you guys have multiple chambers to run this? Yeah. So we
Dr. Emily Witt:
thankfully had 24 chambers.
Dr. Barkha Yadav-Samudrala:
Wow.
Dr. Emily Witt:
We had only 10 chambers. So I was running like 30 animals, but in three separate sessions. So yeah, we were very fortunate to have 24.
Dr. Barkha Yadav-Samudrala:
Yeah, that is a big jump. So how long does this entire experiment take? Once you start running your animal?
Dr. Emily Witt:
That definitely depends on your experimental question. For ours. We were doing a combination of self administration followed by a period of extinction or abstinence in the home cage. So we did self administration for either 10 or 12 days, and then extinction would be roughly 14 to 15 days, or if you were doing abstinence, it would be closer to 35 or 40 days. So combine That's how long
Dr. Barkha Yadav-Samudrala:
it's a long experiment.
Dr. Emily Witt:
Yes, it is, but worth it. Yeah.
Unknown:
Yeah, good data, that is always the end goal. So is there any fun fact you would like to share about self administration?
Dr. Emily Witt:
Yeah. So this kind of relates to the principle of operant conditioning was kind of what it popularized maybe by BF Skinner, if you're familiar with the Skinner box, self administration box is essentially a Skinner box. And he was very famous for doing pigeons. And apparently, in, like, the 1944 time period was World War Two, he was funded by the government to have pigeons learn, somehow to guide bombs, essentially, they had like a screen, and it would have a target on it that the pigeons were trying to pick on the target. Even if they pick the target, it would drop a seed. And if the target like shifted, they would still be picking it. And some kind of sensor would call, like, be sent to the bomb to have it redirect based on where they were picking on the screen. Yeah, apparently it didn't work. And BF Skinner was known for saying no one would take them seriously, which I think is pretty funny. That's just sounds ridiculous. But it was prior to computer guidance. So yeah, trying what you can.
Dr. Barkha Yadav-Samudrala:
Yeah, but I'm kind of glad it didn't work dropped.
Dr. Emily Witt:
Can you imagine?
Dr. Barkha Yadav-Samudrala:
Yeah, I think some of the great ideas comes through these crazy experiments.
Dr. Emily Witt:
Exactly. Yeah. Well, what if we could do the same thing that pigeons are doing with computerized things? So, you know,
Dr. Barkha Yadav-Samudrala:
that would be totally possible. Now?
Dr. Emily Witt:
Yeah, that is one of the things that people are proposing is like a replacement for animal models is computerized. Right. I don't think that'll be coming soon. Because you have to know the outcome. Before you can program it. So yeah, yeah.
Dr. Barkha Yadav-Samudrala:
So now that you mentioned I was reading somewhere. I think it was in Spain, where they developed a heart tissue using spinach leaves. Oh, wow. Yeah.
Dr. Emily Witt:
Is that an article? You should send that to me?
Dr. Barkha Yadav-Samudrala:
Yeah, I will. I will. But I found like, if there is a way probably in like 20 years from now, if we could like, like, develop actual organs that would completely shut down animal research, even organoids, for that matter.
Dr. Emily Witt:
Yes. Yeah. We think there's ideas in the current lab on men of starting organoid projects. Oh, so we'll see how that goes.
Dr. Barkha Yadav-Samudrala:
Wow. That's interesting. Well, so my final question to you would be, are there any articles or protocols that I could link in the description for our listeners, follow upon?
Dr. Emily Witt:
I have my favorite one. Let me pull it up. So I can read that. It's a review. It's called behavioral assessment of drug reinforcement and addictive features in rodents in overview, and that's by Sanchez segura. I've probably pronounce it wrong and spangle, I believe, okay. And it's just a really great review of all the different things you can do with self administration and operant conditioning. And then it also has some really nice visual cartoons, which are just kind of fun to look at and get your the idea of operant conditioning through those. I think it's I gave it to any undergrad that was working with me in the lab, and I found it really useful.
Dr. Barkha Yadav-Samudrala:
Okay, well, I will make sure to link that down in the description. And with this, I'm going to end today's episode. And thank you so much, Emily, for being here with us today. Thank you. Yeah, and guys, please make sure to check out coverage to cut and I will catch you guys next week on another episode. And in meanwhile, if you guys have any suggestions about topics or if you would like to get featured on this podcast and talk about something, please email me at Barkha at Nerdrx podcast.com. And remember, it's good to hear