Institute for Behavioral Genetics

What rats can tell us about the opioid crisis

Rachel Sauer — Mon, 14 Jul 2025 13:30:00 +0000

What rats can tell us about the opioid crisis Rachel Sauer Mon, 07/14/2025 - 07:30

Blake Puscher

̽��Ƶ scientists estimate the heritability of opioid use disorder with a rodent study

Opioid use disorder is an ongoing global health crisis. In the United States alone, almost 108,000 people died from drug overdose in 2022, and about 75% of those deaths involved opioids.

Although many factors contribute to this crisis—and there are many approaches to addressing it as a result—one important line of research is into the genetic factors that increase people’s risk for developing an opioid use disorder (OUD). Once these risk factors are known, doctors may be able to prescribe opioids more strategically to people at higher risk of OUD, and such individuals could make more informed choices.

In recently published research, scientists from the University of Colorado Boulder—including Eamonn Duffy, Jack Ward, Luanne Hale, Kyle Brown and Ryan Bachtell of the Bachtell Laboratory, and Andrew Kwilasz, Erika Mehrhoff, Laura Saba and Marissa Ehringer—tested the influence of genetics on opioid-related behaviors, which include OUD. Specifically, they looked at its heritability by conducting an experiment in which rats were given the ability to self-administer oxycodone, a semi-synthetic opioid that is used medically to treat pain.

̽��Ƶ researchers tested the influence of genetics on opioid-related behaviors, specifically looking at its heritability by conducting an experiment in which rats were given the ability to self-administer oxycodone, a semi-synthetic opioid that is used medically to treat pain. (Photo: Jon Anders Wiken/Dreamstime.com)

Experimental design

More than 260 inbred rats from 15 strains were used for the study. In this case, an inbred strain is defined as a population produced by 20 or more generations of brother-sister mating. This was important for the study because the rats within inbred strain are isogenic: “They’re almost like clones; their genomes are identical, except for the X and Y chromosomes between males and females,” Duffy explains.

Like the use of identical-twin research involving humans, this makes the results more reliable. In a twin study, most differences between twins are caused by their environment, so researchers can determine the genetic influence on a trait by how much it varies. Similarly, within an inbred strain, most individual differences are caused by sex differences, and this provides insight into the importance of biological sex to a given trait. Between inbred strains, differences are attributable to either the strains’ different genes, sex differences, or a combination of the two.

The animals in the study could self-administer the oxycodone using levers, so their behaviors could be measured. There were two retractable levers in the testing chamber: one active, which would give the rats a dose of oxycodone after being pulled, and one inactive, which would do nothing.

After the active lever was pulled, there was a cooldown period of 20 seconds, during which time pulling the lever would not dispense another dose. Regardless of whether pulling a lever had an effect, it would be recorded. This allowed researchers to measure two substance-use behaviors in addition to the total amount of oxycodone consumed. These variables were referred to as “timeout responding” and “lever discrimination.”

Timeout responses were pulls on the active lever that happened during the cooldown period. Lever discrimination was a measure of how often rats pulled the inactive lever. Both essentially tracked the rats’ ability to self-administer substances in a regulated manner, although lever discrimination could have other associations. Attempting to get more oxycodone very quickly (timeout responding) and attempting to get it in an illogical way (low lever discrimination, especially once the animals had time to learn how the levers worked) are signs of dysregulated drug use.

These measures are important in addition to total dosage because the rats naturally consumed more oxycodone as they developed a tolerance to the drug, making it difficult to characterize their drug use on that basis alone. “With addiction,” Duffy says, “it’s a complicated story. They’re developing tolerance, and they’re showing dysregulated use.”

Push the lever, get the oxycodone

The tests were split into two phases: acquisition and escalation. Although the number of daily doses the rats received generally increased over time, especially between the two phases, their self-administration behaviors varied significantly by strain.

For example, in the escalation phase, the females of one strain pushed the lever for a total oxycodone dose of less than 100 mg/kg, whereas rats of another strain took a total of about 300. There was also variation between males and females within a strain, though not always: In some strains, males and females consumed a similar amount of oxycodone, while in others, consumption was notably divergent, with males consuming around 200 mg/kg more oxycodone overall.

Once the genetic factors that increase people's risk for developing an opioid use disorder (OUD) are known, doctors may be able to prescribe opioids more strategically to people at higher risk of OUD, and such individuals could make more informed choices. (Photo illustration: iStock)

This is evidence for a strain-sex interaction, meaning that the rats’ substance-use behaviors were determined by a combination of genetic background and biological sex, not either alone, according to the researchers. Although the obvious explanation for this would be different genes encoded on the sex chromosomes of the various strains, this isn’t necessarily the case.

“Some of our collaborators in San Diego have performed several genetic mapping studies,” Duffy says, “and they found that the Y chromosome didn’t appear to play much of a role in regulating behavioral traits.”

It is possible that X-chromosome genes are a greater factor. However, the biggest influence would probably be sex hormones or related differences, Duffy adds. For example, according a separate study, the sex hormone estradiol can increase oxycodone metabolism indirectly by raising the concentration of a protein in the brain.

Moreover, Duffy says, “there could be developmental aspects to the sex difference, so seeing if they’re exposed to testosterone versus estrogen as they’re growing up, that may affect how their brain is wired.”

Several other strains showed notably divergent behaviors. Some strains were fairly stable in their use, while others increased their oxycodone intake rapidly during the acquisition phase. Lever discrimination also varied by strain, with one strain increasing its lever discrimination quickly, for example, while another failed to increase its lever discrimination much over time.

The biggest discovery that emerged from the research was the discovery of how heritable several behaviors related to opioid use are.

The influence of genetics

Heritability is a measure of what part of the variation in a group is due to genetic or heritable characteristics.

“With heritability,” Duffy explains, “when you’re looking at everything that goes into some kind of trait, like opioid use disorder, the average genetic component will be your heritability. You also have environmental influences, which could be things such as diet.”

Taking OUC as an example, variation might be understood qualitatively in terms of how destructive the effects of drug use are on individuals, from having minimal effect on people’s lives to potentially causing overdoses and death, Duffy adds.

If the heritability of OUD were 0, the fact that some people use the drug safely and others die because of it would be explained entirely by non-genetic factors. If the heritability of OUD were 1, this fact would be explained entirely by genetics. However, as with most traits, OUD appears to be caused by a combination of genetic and environmental factors.

According to the study, measures of oxycodone intake ranged between 0.26 and 0.54 heritability. The high end of this range is total oxycodone intake over the course of the experiment, while the low end is change in intake (increase in intake over the acquisition phase). The other behavioral phenotypes had heritability scores of 0.25 to 0.42, with timeout responding being more heritable than lever discrimination.

“̽��Ƶ half of that variability is due to genetic background,” Duffy says, referring to total intake. “That’s really strong heritability.” However, because these data come from rats, the heritability of these behavioral phenotypes may be different in humans. “We’re not going to capture everything about OUD in a rat model, but we can capture specific aspects and use that to put together a bigger picture.

“OUD is hard to study in humans because there aren’t as many people using opioids as alcohol or nicotine, and of that smaller population, we also have people using several types of drugs, so it’s harder to calculate these heritability values, but I believe ours do fall within the range for opioid dependence and opioid use disorder in humans.”

“With addiction, it’s a complicated story. They’re developing tolerance, and they’re showing dysregulated use.”

It's also important to recognize that heritability is a population-level statistic. This means that it does not represent the chance for any individual to develop a trait, even if that trait could be inherited from the individual’s parents. However, a higher heritability of some trait would correspond to a greater resemblance between parents and offspring in that respect throughout the population, Duffy says.

What genes contribute to OUD?

While it is useful to know how heritable opioid use disorder is, meaningfully assessing the risk for individuals requires knowing what genes contribute to it. This study doesn’t identify these genes, but progress has already been made to this end.

“There’ve been a number of studies in humans that have found that these SNPs, or single nucleotide polymorphisms, are associated with your risk of developing conditions like opioid dependence or opioid use disorder,” Duffy says. “There’s another group that is performing some genetic mapping in outbred rats, and that’s going to be the next stage of this project for us as well.”

One potential gene influencing OUD in mice is an SNP in the Oprm1 gene, which is explained in the study to affect the brain’s response to reward-related behavior generally and analgesics like oxycodone specifically. Common Oprm1 SNPs have also been associated with dysregulated use of an opioid in humans, specifically heroin.

Once relevant SNPs are identified, however, the situation remains complex. “It’s not going to be a simple answer,” Duffy says. “Like, you have this one SNP in Oprm1 and that’s going to increase or influence your risk for OUD. It’s probably going to be a multitude of SNPs, and those additive effects are going to influence the risk for this disorder.”

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̽��Ƶ scientists estimate the heritability of opioid use disorder with a rodent study.

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Detecting cognitive decline before its symptoms start

Rachel Sauer — Wed, 13 Nov 2024 20:24:58 +0000

Detecting cognitive decline before its symptoms start Rachel Sauer Wed, 11/13/2024 - 13:24

Daniel Long

In his research on the brain, Daniel Gustavson looks for clues about when cognitive decline begins

According to Daniel Gustavson, assistant research professor in the Institute for Behavioral Genetics, much of the research on cognitive decline starts late.

“A lot of studies of older adults—too many, in my opinion—focus on when some cognitive decline has already happened,” he says. “It's clear that a lot of the disease, or even just normal aging, has already taken place by the time somebody comes into a clinic and says, ‘I'm worried about my brain.’”

Gustavson wants to dig deeper into the timeline and see if cognitive decline can be spotted before its telltale signs arise. A paper he coauthored and recently published in Neurobiology of Aging makes headway toward accomplishing that goal.

̽��Ƶ researcher Daniel Gustavson notes that a lot of cognitive decline, or even just normal aging, has already taken place by the time "somebody comes into a clinic and says, ‘I'm worried about my brain.’”

The cognitive gas tank

Gustavson’s study—which used twin research, genetic analysis and magnetic resonance imaging (MRIs), among other methodologies—examines the relationship between brain reserve in middle age and executive function later in life.

“Brain reserve,” says Gustavson, “is a bit like a gas tank. You have a certain amount of gas built up when you’re a young adult, when your brain is at its healthiest, and as you age, you start to lose some of that fuel.”

Executive function, he adds, refers to complex goal management or attentional control. “It captures higher-level cognitive processes, where you have to be controlling other sub-processes.”

An example of executive function in action is asking someone to memorize and reorder a string of letters and numbers.

“You might have people listen to a list like X, six, B, Y, seven, J, and then they’d have to remember that list in their head and repeat the numbers back in numerical order and the letters in alphabetical order,” Gustavson says. “It’s a little more complicated than just repeating what someone said.”

Using data from the Vietnam Era Twin Study of Aging (VETSA), which includes more than 1,600 subjects who have undergone various cognitive assessments at regular intervals over the past 20 years, Gustavson and his coauthors concluded that higher brain reserve at the age of 56 was associated with better executive function at the age of 68.

Looks can be revealing

Brain reserve, says Gustavson, is a proxy for brain thickness, and brain thickness is determined through MRIs.

To analyze the hundreds of MRIs of VETSA subjects, Gustavson and his coauthors used a machine-learning algorithm developed by James H. Cole, professor of neuroimage computing at the MANIFOLD Lab, which was trained in much the same way Google trains its search algorithms.

“You can train it over and over again,” Gustavson says. “The more data you have”—that is, MRIs—“and the more times you tell it, ‘You were wrong this time. You were right this time,’ the better it gets at classifying this brain as one age versus that brain as another age.”

The algorithm assesses plump, padded brains as younger and atrophied, motheaten brains as older, regardless of the chronological age of the people in whose heads those brains reside. That means, for example, that a 56-year-old can have a brain that appears 60 and a 60-year-old can have a brain that appears 56.

And this matters, Gustavson says, because how a brain looks in an MRI predicts its executive function years later.

“Controlling for their actual age, people with younger-looking brains had much shallower decline in executive function over the subsequent 12 years, and people whose brains appeared older than average had steeper drops in executive function.”

Yet the cause of this discrepancy—genetics? environment? trauma?—is something the algorithm alone can’t explain. That’s where twin research comes in.

Same genes, different story

One of the benefits of twin studies like VETSA, Gustavson says, is their ability to separate environmental influences on a person’s health—things like diet, exercise and place of residence—from genetic influences.

“Brain reserve is a bit like a gas tank. You have a certain amount of gas built up when you’re a young adult, when your brain is at its healthiest, and as you age, you start to lose some of that fuel,” says Daniel Gustavson. (Illustration: iStock)

“Those two things aren't fully separable, but basic twin studies give us some idea of how inherited different constructs are—not only cognitive abilities, like memory or speed, but also changes in those abilities. Twin studies help us quantify how much those changes are due to genetics and how much are due to environment.”

If one twin experiences cognitive decline faster than the other, in other words, researchers can confidently point to environment as the reason, since twins share the same genes.

But twin studies can go only so far, Gustavson says, as they tend to paint with a broad brush. “You often can't pinpoint specific genes or specific environments that matter, because it's all statistical.”

That’s why Gustavson and his team incorporated genetic analyses in their study. They wanted a higher-resolution snapshot of the genetic influences on cognitive decline, specifically by seeing if the APOE genotype, which is strongly associated with Alzheimer’s, predicted a drop in executive function.

What they found is that, although APOE alone did not fully explain changes in subjects’ executive function over time, those subjects’ genes taken as a whole did.

“Most of the association between people's brain health and their future cognitive decline, about two-thirds, was explained by genetics,” Gustavson says.

But that’s not to dismiss the other third as inconsequential.

“Things like healthy lifestyle, diet, smoking and alcohol use, social engagement—those things don't seem like they relate to cognitive changes, but they might impact your brain health in the first half of your life, and then your brain health in midlife will impact your cognition later,” says Gustavson.

The fourth wave

Gustavson and his fellow researchers just completed the fourth wave of data collection, when the VETSA subjects were 74 years old, and are therefore currently working to build upon their findings.

“We would like to expand our models to capture the cognitive changes even further out,” he says.

Gustavson would also like to deepen his understanding of what exactly the brain-age algorithm is detecting. “Is it capturing something new to midlife, or is it capturing something from young adulthood, the consequences of which are only becoming apparent in midlife?”

He suspects it’s the latter, but he’s not yet sure. “I really want to look at that in more detail.”

Jeremy A. Elman, Chandra A. Reynolds, Lisa T. Eyler, Christine Fennema-Notestine, Olivia K. Puckett, Matthew S. Panizzon, Nathan A. Gillespie, Michael C. Neale, Michael J. Lyons, Carol E. Franz and William S. Kremen contributed to this research.

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In his research on the brain, Daniel Gustavson looks for clues about when cognitive decline begins.

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Top illustration: iStock

ADHD and reading disability often occur together, study finds

Anonymous — Thu, 17 Oct 2024 14:56:38 +0000

ADHD and reading disability often occur together, study finds Anonymous (not verified) Thu, 10/17/2024 - 08:56

Daniel Long

It’s surprisingly common for children to have both conditions, ̽��Ƶ researcher Erik Willcutt argues in a recently published paper

According to a paper coauthored by Erik Willcutt, professor of psychology and neuroscience at the University of Colorado Boulder and faculty fellow of the Institute for Behavioral Genetics, many children with attention-deficit/hyperactivity disorder (ADHD) also have reading disability, and vice versa.

“A lot of kids tend to have both learning and attentional difficulties,” says Willcutt, a clinical child psychologist by training. “Similarly, many children with reading disability also experience broader learning difficulties in areas such as math and writing.”

This research marks a shift in the clinical understanding of learning disabilities.

In recently published research, Erik Willcutt, a ̽��Ƶ professor of psychology and neuroscience, finds that many children with attention-deficit/hyperactivity disorder also have reading disability, and vice versa.

“Twenty-five years ago, we all went into an assessment with a child thinking we had to figure out what the diagnosis is.”

“The” diagnosis—singular.

“Back then, it was always kind of surprising if a child met criteria for more than one diagnosis. We’d think, ‘Maybe we’re just wrong, and we’ve got to figure out which diagnosis is correct.’”

Yet, as research has progressed, this either-or thinking has transformed into something more like both-and thinking.

“We’ve realized over time, there are a lot of kids that really do seem to have more than one diagnosis, and that in many cases both diagnoses would benefit from treatment.”

When one diagnosis complicates another

The phenomenon of multiple diagnoses for one person is called comorbidity, a term “that came out of classic medical literature where people could have more than one illness at the same time,” says Willcutt. “For example, heart disease frequently co-occurs with other physical conditions such as diabetes, and this may mean that treatment of the heart disease is complicated by the diabetes or another co-occurring illness.”

It’s the same idea with reading disability and ADHD. “That comorbidity suggests that a child's difficulties extend beyond what they would be if that child had just reading disability.”

Reading disability, Willcutt points out, doesn’t simply mean difficulty reading. It means unexpected difficulty reading, with the expectations being based on a child’s education.

So, a child who struggles to read but hasn’t had an adequate reading education may not have reading disability. Perhaps that student struggles because he or she hasn’t grown up around books, or hasn’t been read to, or hasn’t been given adequate reading instruction. For a student such as this, difficulty reading may not be a disability so much as the natural consequence of a less-enriched reading environment.

It's the children who have had an adequate education and still underachieve in reading who may have reading disability. And if those kids also happen to have ADHD, their reading disability will likely be harder to manage, just as heart disease becomes more challenging for someone who also has diabetes.

“Individuals with more than one disorder often differ in important ways from individuals with a disorder in isolation, with the comorbid group frequently experiencing greater symptom severity, more extensive and severe functional and neurocognitive impairment, and poorer long-term outcomes,” Willcutt and co-author Stephen A. Petrill state in their paper.

Externalizing and internalizing behaviors

Researcher Erik Willcutt notes that reading disability doesn’t simply mean difficulty reading. It means unexpected difficulty reading, with the expectations being based on a child’s education.

There is a range of behaviors associated with reading disability and ADHD, Willcutt explains, some of which are “externalizing” and some of which are “internalizing.”

Externalizing behaviors are those that children express outwardly—“things like aggression, delinquency or conduct problems,” says Willcutt—whereas internalizing behaviors “are more internally focused—so if you feel anxious or you feel depressed or withdrawn.”

Willcutt says that reading disability and ADHD frequently co-occur with both internalizing and externalizing behaviors, but the specific profile varies among children. One student with comorbid ADHD and reading disability may continually show up late to school and disrupt class, whereas another student with the same diagnoses may be quiet and anxious.

“And there are some different behavior clusters that seem to really matter,” Willcutt adds. “The kids who have reading disability and ADHD along with early aggressive or delinquent behaviors tend to be a subgroup that is at higher risk for more severe antisocial behaviors during adolescence. On the other hand, students who have ADHD and reading disability along with internalizing symptoms often show pronounced difficulties in the classroom because they are really anxious about their academic performance.”

Assessment and treatment

Willcutt says that one key takeaway from his and Petrill’s study is that comorbidity matters and is much more common than previously thought. “At least 25% of kids who have ADHD have a learning disability, which is much higher than we would expect by random chance.”

Willcutt therefore hopes those who read his and Petrill’s study, particularly clinicians, adjust their assessment practices in a way that addresses the potential for comorbid diagnoses.

We’re at the point of saying when a child has ADHD and reading disability, both conditions really warrant interventions. Rather than trying to decide which is more important, we should really target both of them by providing the optimal intervention for reading disability and the optimal intervention for ADHD.”

“If you’re assessing learning disabilities, it’s really important to also assess whether a child has attention problems, anxiety or conduct difficulties along with that. For clinicians who specialize in the assessment of ADHD, it's critical to include a screening measure to determine whether the child may also have learning problems. Our results suggest that it may matter quite a bit if they have a comorbid diagnosis.”

For the field more broadly, Willcutt hopes that his and Petrill’s work prompts other researchers to study treatments for comorbid learning disabilities and attentional difficulties.

“We’re at the point of saying when a child has ADHD and reading disability, both conditions really warrant interventions. Rather than trying to decide which is more important, we should really target both of them by providing the optimal intervention for reading disability and the optimal intervention for ADHD.”

In other words, if a child has both reading disability and ADHD, treating only one will likely have little to no effect on the other.

“Reading intervention might really help with the reading, but it may not address some of the other concerns that are also getting in the way for that child.”

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It’s surprisingly common for children to have both conditions, ̽��Ƶ researcher Erik Willcutt argues in a recently published paper.

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