Dr. Amy Lasek studies the biological foundation of alcohol and drug addiction, including the neurobiological differences between men and women as they pertain to alcohol use disorder. Dr. Lasek spoke about her efforts to understand the mechanisms of binge drinking behaviors in women, as well as the important role her drug discovery collaborators play in bringing the basic science of addiction a step closer to a usable form of therapy.
Amy Lasek, PhD
Associate Professor
Departments of Psychiatry and Anatomy and Cell Biology
University of Illinois at Chicago College of Medicine
Gregory Thatcher, PhD
Professor, Pharmacology and Toxicology
R. Ken and Donna Coit Endowed Chair in Drug Discovery
R. Ken Coit College of Pharmacy, University of Arizona
Manel Ben Aissa, PhD
Research Assistant Professor, Department of Pharmaceutical Sciences
Assistant Director, UICentre
University of Illinois at Chicago College of Pharmacy
To learn more about the UICentre, visit https://centre.pharmacy.uic.edu
Learn more about the CCTS Pilot Grant program at ccts.uic.edu/funding
If you would like to see your interdisciplinary team featured on the podcast, reach out to me at laurenw@uic.edu.
Interested in volunteering to participate in health research? Today’s researchers want to make sure that treatments and cures are designed for everyone’s unique needs. Are you ready to make a difference? Learn more at go.uic.edu/healthresearch.
The University of Illinois at Chicago Center for Clinical and Translational Science is supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR002003. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
0:00. [TEASER CLIP, Lasek]
We really are coming at this from a very molecular and cellular level- what's happening in the brain with chronic alcohol exposure? And also, what are factors in the brain that might contribute to a predisposition to drink excessively?
0:20 [Voiceover Introduction]
Welcome to Collaborative Endeavors, a podcast about how scientists from different areas of research come together to tackle big health challenges, leading to better therapies and healthier communities.
Dr. Amy Lasek is an associate professor in UIC’s department of psychiatry with a joint appointment in anatomy and cell biology. Her lab is interested in understanding the biological foundation of alcohol and drug addiction using molecular, cellular, genetic, and behavioral approaches in rodents. They also study neurobiological differences between men and women as they pertain to alcohol use disorder, what many of us refer to as alcoholism.
In 2018, Dr. Lasek was awarded a CCTS pilot grant for a project examining a new therapeutic approach to reduce binge drinking in women. Treatment options for alcohol use disorder are limited across the board, but this is especially true for women, who are often underrepresented in clinical studies. Dr. Lasek spoke about her efforts to understand the mechanisms of binge drinking behaviors in women, as well as the important role her drug discovery collaborators play in bringing the basic science of addiction a step closer to a usable form of therapy.
01:30 Amy Lasek:
My training is in molecular and cell biology. I got my PhD at Cornell University in New York City at the Weill Graduate School of Medical Sciences. My primary training was in molecular biology. And so I actually wasn’t doing neuroscience, I was doing cancer research. I was interested in signaling pathways involved in cancer. And that sort of gave me a really nice molecular and cellular background for the studies that I do now. And then in 2003 I actually switched to neuroscience because I thought there were a lot of open areas in neuroscience and especially molecular and cellular neuroscience. I guess my main fascination with that was, how do you manipulate a specific gene in a specific brain region and cause a change in behavior? And so that to me was a really interesting question and especially related to addiction. And sometimes in society we still think addiction is something that has to do with a moral failure or some kind of lack of willpower, for instance. But really the addiction is based on biology and it's based on both genetic and environmental factors. And I just thought - what if you manipulate a specific gene or a specific signaling pathway in the brain? How does this contribute to behaviors related to drug addiction?
03:23. Voiceover
A little over 5% of the population suffers from an alcohol use disorder, which is basically defined as the inability to quit drinking, drinking to excess or drinking despite negative consequences. Binge drinking is a particularly prevalent form of alcohol use that leads to serious adverse health outcomes for women, including increased risk of breast cancer, organ damage, and mental illness.
03:47 Lasek
So, alcohol drinking, excessive drinking- or even sometimes moderate levels of drinking- can lead to increased risk of breast cancer. There's an increased level of cognitive impairment with alcohol use in women and also liver damage and cardiac outcomes. So it’s important to study women and know- what's the biology that's driving alcohol drinking in women versus men? Because it may be slightly different biology that's driving these differences in drinking.
We're really basic scientists doing research on a clinical question, but we try to lean in a translational direction so that we can find new drug targets for treating alcohol use disorder. And so we have a number of different projects and one of the projects that we're working on has to do with looking at sex differences in alcohol drinking and alcohol use disorder. And one of the things we know from the clinical literature is that women are more likely to transition from sort of casual drinking to actually having an alcohol problem and women are also more sensitive to the detrimental effects of alcohol.
05:12 Voiceover
Dr. Lasek went on to describe the research study that laid the foundation for her CCTS pilot project.
05:17. Lasek
We work with mice. We started out this project first just comparing what happens in between males and female mice when you look at it in a binge drinking test. They're getting enough alcohol that they're that they're showing the pharmacological effects of alcohol. So this is important because we want them to be drinking in a sense in a way that humans would drink, where they would be binge drinking and drinking enough to become intoxicated. So when we compare the males and the females, we found that the female mice actually drank more than the males. And this is consistent with what's been out there in the literature for a while, but it was sort of the first time we had done it with this specific binge drinking test. And then we decided let's figure out why the females are drinking more than the males.
And so one of the reasons they could be drinking more is because of differences in their hormones, and specifically estrogen and progesterone. And so we removed the ovaries from the mice and then we looked at their drinking behavior. And when we compared the females without ovaries to the males and to the gonadally intact females, they actually drank less. So they drank as much as the males but not at the high levels that females with ovaries drank. So that suggested to us that the hormones are involved in alcohol binge drinking in females.
So that was sort of the basis for trying to understand really the underlying biology of this. And we did couple different things. One thing we did is we looked in a reward region of the brain -one of the areas called the ventral tegmental area, and this is where the dopamine neurons are located. Dopamine neurons actually are thought to be involved in the rewarding and reinforcing properties of drugs of abuse. And we saw that there are estrogen receptors in the in the dopamine neurons in the ventral tegmental area, in both males and females. So both sexes actually make estrogen receptors in their brain and are responsive to estrogen. But the interesting thing was when we knocked down a specific estrogen receptor known as ER-Alpha, we actually reduced drinking in the females but not in the males. So even though both the females and the males make these estrogen receptors in their ventral tegmental area we only had an effect of reducing the receptors in the female. So, again, this was sort of a really interesting finding that these estrogen receptors may only be in this region active in the females.
And we've also done some further studies… where we found that alcohol can stimulate the activity of these dopamine neurons and when estrogen levels are high the activity of these neurons is higher in response to alcohol. So, again, estrogen is sort of implicated in this response of the dopamine system. So then, this kind of gave us an idea of where in the brain this might be occurring- or one of the areas of the brain of where it's occurring- and mechanisms related to dopamine. But in terms of a translational aspect, we were really interested determining- could we treat females with some kind of drug that blocks estrogen receptors and see an effect on alcohol drinking?
09:05 Voiceover:
Let’s take a step back for a minute. Researchers who study the molecular biology of a disease, like Amy Lasek, typically focus on a protein and then perform genetic manipulations to increase or decrease its expression. In turn, this can reduce the disease condition in their model.
While this is an important step in validating a target or pathway, these techniques cannot be used to create drug therapies. Developing a compound that might mimic the results of a genetic deletion is an entirely different skill set. And even when investigators properly orient their research towards developing a therapy, the process of translating the basic science of a disease to a clinical intervention is so daunting that it is appropriately referred to as the “valley of death.”
To overcome this challenge, Dr. Lasek’s team partnered with Dr. Gregory Thatcher, currently professor of pharmacology and toxicology at the University of Arizona’s College of Pharmacy. In his former position at UIC, Dr. Thatcher founded UICentre, a campus-wide disease-agnostic drug discovery unit focused on small molecule drug discovery. The center’s collaborative organizational model has evolved to bring together experts with varied skill sets including project management, bioassay development, high throughput screening, and drug metabolism and pharmacokinetic studies.
10:23 Lasek
Actually I think the reason I got connected with Dr. Thatcher was because I gave a talk in the College of Pharmacy on our work in in alcohol use disorder and estrogen and I think that was sort of the initial connection. And then we have this idea that we should collaborate because he was very interested in estrogen receptors in the brain and designing compounds that actually could get into the brain and work in the brain. So that was sort of the initial connection. Then we just decided, well this would be a perfect opportunity to collaborate because we had this test set up. We had some evidence that estrogen was involved in binge drinking and females and so we could use his compounds to do these experiments to see if we could reduce binge drinking. So that was sort of a nice like perfect intersection of our strengths: my behavioral and molecular neuroscience and his medicinal chemistry background and interest in estrogen receptors in the brain.
He has developed what are called selective estrogen receptor degraders. And those are drugs that actually can lead to the down-regulation of estrogen receptors. And his primary reason for developing these originally was for breast cancer treatment. So one of the drugs that's out there that that’s FDA approved for metastatic breast cancer is a selective estrogen receptor degrader- abbreviated SERD- called fulvestrant. And this is typically used to treat women with post-menopausal women with metastatic breast cancer, but this drug doesn't really get into the brain very well. And so for our purposes, we couldn't really think of using fulvestrant as sort of an orally bioavailable drug to reduce binge drinking in females. So Greg Thatcher’s group actually developed a SERD that is blood-brain barrier penetrant, so it can get into the brain. And we decided to do a series of experiments where we treated female mice with the selective estrogen receptor degrader that he developed and then tested the binge-drinking that I was talking about earlier in female mice. The interesting thing is we were able to reduce binge drinking after a few treatments with the SERD in the female mice. This suggests that oral bioavailable and brain penetrant selective estrogen receptor degraders can potentially have some therapeutic impact.
13:16 Voiceover
While Dr. Thatcher was not available to contribute to this episode, I was able to speak with UICentre’s assistant director, Dr. Manel Ben Aissa. She elaborated on Dr. Thatcher’s contributions to Dr. Lasek’s project, how drug repurposing works and the role of drug discovery units like UICentre when it comes to the potential identification and development of new pharmaceutical therapies.
13:40 Manel Ben Aissa
My name is Manel Ben Aissa and I am assistant director at UI Centre for drug discovery. I'm also a research assistant professor in the department of pharmaceutical science at UIC. Through UI Centre I am involved in different stages of drug discovery from early-stage to late-stage, so I do assay development, screening and later stage mechanisms of action or proof-of-concept studies for in vivo validation.
I am not specialized in addiction, but when Amy Lasek approached us at UICenter she was seeking a novel target for addiction, especially in females treated with estrogen to increase the behavior of binge drinking females. And when she knocked down the ER receptor in the brain, that behavior decreased a lot. So because Dr. Thatcher had 20 years’ experience in the development of endocrine therapy for breast cancer. So UICentre looked to repurpose this class of compounds to try to treat addiction and specifically the binge drinking behavior in females. So we have different classes of compounds at UICentre that were developed by Dr. Thatcher. He has SERDS, that made it to clinical trial. And the good thing about this class of compounds is that they are brain bioavailable. It means that other than cancer we can use them to target ER in the brain. And Dr. Lasek discovered this novel target, so we wanted to see if potentially we can repurpose this class of drugs to treat addiction in females specifically.
So usually the PIs know their projects very well and they are at different stages- they are early stage or later stage with more validation- and they know more about the target and they know how to do the assays. But to discover drugs is another thing. So usually the collaborator comes to us with a good assay that is not scalable, for example, to do high throughput screening to identify novel drugs. So we can assist them to look at the assay and to up their target if it's druggable or not. If you can develop an assay, if we can go to the next step to do screening, we can help them with medicinal chemistry to optimize the compounds that were identified from screening. We can also even help them at later stages of preclinical validation because we have a med-chem component at UICentre. So we can look at pharmacokinetics of drugs, if they are druggable or not, if they can be available when we treat the animals… so we can help at different stages of drug discovery.
16:45 Voiceover
Dr. Ben Aissa also stressed the importance of considering sex differences in the development of drugs. Research has shown that biological differences between men and women- that is, differences due to sex chromosome or sex hormones- may contribute to variations seen in the safety and efficacy of drugs, biologics, and medical devices.
17:16 Ben Aissa
I think gender difference or sex difference are usually omitted from clinical trials, and try to recognize that there is a difference in many diseases. Like for example, in Alzheimer’s disease you have more women that will develop Alzheimer's disease. It's important to try to consider the sex difference in clinical trial to remove the bias during validation of drugs.
17:42 Voiceover:
While the use of SERDs to address binge drinking behaviors shows promise, an intervention involving the manipulation of estrogen in the brain is not without its risks. Dr. Lasek explained some of the drawbacks to this approach as well as potential new areas of exploration.
18:00 Lasek
There are complications associated with any drug and it's important to investigate whether this would have any other effects on females, given what we know about estrogen receptor blocking drugs in premenopausal females.
Estrogen receptors interact with other proteins in the cell and again, this this might be involved in that response to alcohol. If we can block either the estrogen receptors or a protein that interacts with estrogen receptors, maybe we can decrease drinking and decrease that enhanced sensitivity to alcohol. So it's a way of coming at it from a different question, you know, it's sort of like from the side- okay, what are the other interacting proteins?
If you give, for instance, tamoxifen to women there are psychiatric effects of that. People can become more depressed when they're on tamoxifen because estrogen receptors play an important role in in anxiety and depression, as well. And so you want to be careful maybe not directly targeting those estrogen receptors, but maybe targeting something in the pathway that is perhaps more specific to the response to alcohol.
One of the predictions of this is that during different phases of the menstrual cycle in premenopausal women you would have perhaps a higher propensity to drink more alcohol or binge drink. And there is some data out there that suggests that women in their follicular phase when estrogen levels before ovulation are rising that they consume more alcohol. And so, you know, I think there is some translational aspect to this and you bring up the word awareness and it's not that necessarily we want to start giving women estrogen receptor blockers to reduce their binge drinking but an awareness of – “okay, well I'm at this specific phase of my menstrual cycle, maybe I'm at higher risk” - maybe that awareness will help. Maybe women will think- maybe I can try not to drink as much, try not to let it get out of control. So there, I mean there is a little bit of an aspect of that. The other thing is that in terms of treatment, maybe stabilizing the hormonal fluctuations, in some way, with therapy like estrogen replacement or something like that.
Maybe there are some other things we could look at in humans. For instance, in human blood samples or in looking at genetic variations and estrogen receptors that might be associated with high levels of drinking. And so that would be an area that might be really interesting to pursue is really sort of look at this genetic variation because maybe that would be involved. And I think because they have the samples from human patients that would be really interesting to do in the future.
For me the idea of Team science is really important. I've always loved being part of a team where people bring in different areas of expertise and I participate in many ways in different teams. So I'm part of our Center for alcohol research and epigenetics here at UIC. And what we're doing is trying to understand epigenetic mechanisms that are involved in basically depression and anxiety during withdrawal from alcohol as a way to target that to prevent relapse to drinking. And we bring in a lot of different expertise. I mean, we have the molecular and cellular expertise but the behavioral expertise and then, you know, eventually, perhaps drug discovery once we identify a new target where we can develop drugs based on those targets. I just think you gain so much from being a part of the team and the I think you make more advances that actually have translational relevance when you work as part of a team. But then I'm continuing my focus on the basic science, really. So collaborating with people that do things that I can't do like the electrophysiology, which is a whole different area of neuroscience as more of an idea of getting at mechanisms.
In terms of studying alcohol use disorder, I think it's just really important to think about how can we understand this brain disorder from the basic biology of it and really try to find new ways to help people. So, you know, that's sort of the motivation behind everything we do.
Voice Over Outro:
Collaborative Endeavors is produced by me, Lauren Rieger, on behalf of the Center for Clinical and Translational Science (AKA the CCTS) at the University of Illinois at Chicago.
To learn more about the research discussed in this episode, visit the links in our show notes.
The CCTS is supported by the National Institutes of Health’s National Center for Advancing Translational Science through their Clinical and Translational Science Award. Opinions expressed by guests of the show are their own and do not necessarily represent the views of myself, the CCTS or our funding agencies.
You can find more episodes of Collaborative Endeavors on Apple Podcasts, Spotify, Amazon Music & Google Podcasts. New episodes drop monthly. If you would like to see your interdisciplinary team featured on the podcast, reach out to me via the email address in the show notes.
To learn more about how you can get involved in health research, visit ccts.uic.edu or follow us on Twitter @UIC_CCTS.