The Genetics of Addiction
I often get asked in meetings about the possible passing of the addictive behavior by the attendees to their offspring via genetics. This is a complex issue and the field has now progressed nicely in the understanding of this issue – with rapidly developing understanding of epigenetics . a different form of inheritance . This is nicely described in this recent article from “ The Fix” by Jeanne Swanson which I have copied here. Its pretty self explanatory so here it is in its entirety for your interest . It surely is to me.
In biology class, most of us were taught to believe that specific traits are passed on through our genes: if I have the “Alzheimer’s gene” or the “breast cancer gene,” there’s a probable chance that my son or daughter will carry that gene. However, what about more “complex” diseases like depression, or alcoholism? While alcoholism does tend to run in families—and has a genetic component—how exactly is it passed on?
In recent years, more and more studies are showing that there is another level of inheritance at work: epigenetics. Literally “above the genome,” epigenetic marks are chemical “tags” that can be put on or taken off DNA, and their purpose is to control the expression of genes. Some tags turn genes on, while others turn genes off. These tags come in the form of molecules called methyl groups or acetyl groups, and they can also appear on the outside of the DNA strand. In the nucleus of every cell, the very long strands of DNA coil around proteins called histones; these histones can be more “open” or “closed,” depending on what tags reside on the surface.
These “tags” can be helpful and are very important for many biological processes. For example, in the development of an embryo into a baby, epigenetics plays a huge role in making sure embryonic cells differentiate at the right time and place. Ever wonder how a small handful of cells become heart and lung and brain cells, and all the other cells in our bodies? Since every single cell contains all of our DNA, some genes have to be turned off, while others left on, in order for there to be different types of cells.
However, the epigenome is ever changing; marks can come, and marks can go. In fact, the epigenome is highly sensitive to the environment. Environmental Factors such as diet, stress, and exposure to environmental toxins can alter the arrangement of these tags and cause disease. And, it’s being increasingly shown, disease in not just us, but in our kids, and our grandkids. Groundbreaking—and controversial—studies by epigenetics researcher Michael Skinner at Washington State University have not only brought to the forefront the idea of endocrine disruptors, but that these environmentally harmful chemicals can leave marks on the genome that can be passed on through germ cells—sperm and egg—to next generations. This new field has become known as transgenerational epigenetic inheritance.
And while there are examples of traits that have been inherited across multiple generations in everything from seeds to rodents to humans—DNA methylation patterns in response to environmental toxins, for instance—“no one has looked in terms of drugs of abuse,” says Ghazaleh Sadri-Vakili, an assistant professor at Harvard Medical School and the director of the neuroepigenetics laboratory of the MassGeneral Institute for Neurodegenerative Disease. That is, until now.
Building off this previous work, several recent studies in rodents have, indeed, delved into how drug and alcohol use affects the epigenome of the offspring. While mothers can harm the baby in utero, as well as subject it to stress and abuse as a child, researchers are beginning to ask the question: Can the effects of parents’ substance abuse be felt by their children, even if they stopped using years before?
These new findings suggest that if a parent uses drugs, he or she could pass on that DNA “damage” in the form of inherited epigenetic changes. What’s more, these epigenetic changes can predispose the offspring to not only becoming addicts, but to having to grapple with the behavioral traits that make it so hard to resist the pull of using, like impulsivity and heightened sensitivity to drugs.
THE EPIGENETICS OF ADDICTION
The hallmarks of addiction are tolerance and then, sensitization. Sensitization happens when a user becomes overly sensitive to a drug’s high or rewarding effect; accompanied by intense cravings and often, relapse. Eric Nestler, a leading figure in studying the epigenetic changes associated with addiction, discovered two key transcription factors that remain turned on after using drugs, thereby leading to symptoms of tolerance. (A transcription factor is a protein that parks itself next to a gene and turns it on.)
However, what was keeping the transcription factors around, they themselves being proteins from active genes? “The heightened sensitivity, it turns out, stems from epigenetic modifications of the genes,” Nestler, who is the director of the Friedman Brain Institute at the Mount Sinai School of Medicine, wrote in an article for Scientific American magazine in 2011.
In recent years, Nestler’s lab has conducted a series of studies on rodents that show how cocaine use can affect the genetic activity in certain parts of the brain. In one, he found that chronic cocaine use changes the pattern of acetyl and methyl tags on hundreds of genes within the brain’s reward center; and these changes make these genes more active when subsequently exposed to cocaine. In another paper, they found that chronic cocaine administration dials down the activity of certain molecules that remove acetyl groups, and of certain molecules that add methyl groups—in both cases making the genes more active with more cocaine. Epigenetic modifications have been observed in rats that use alcohol, nicotine, cocaine, amphetamines, and opiates.
Many of these changes are transient, lasting only a few hours after the animal receives the drug. Some last much longer, however; Nestler’s group has seen changes last as long as a month, and they’re looking into even longer times. In fact, if Skinner and others are right, it’s the very long-lasting nature of these epigenetic changes that make them heritable.
In the mid-1800s, the theory of natural selection replaced the idea initially proposed by biologist Jean-Baptiste Lamarck, who believed that acquired characteristics could be inherited. Now, study after study is showing that by some mechanism, acquired traits—like sensitivity to drug exposure—can, in fact, be passed from parent to offspring. While several well-cited studies have shown epigenetic inheritance of disease, studying transgenerational effects in drug addiction is in its infancy.
Yasmin Hurd, a professor at the Mount Sinai School of Medicine, published a study early this year showing that adolescent rats that were exposed to THC had first-generation (F1) offspring who were, among other telltale behaviors of addiction, more likely to use heroin compulsively. On a molecular level, parental THC exposure was associated with gene expression changes in the cannabinoid, dopamine, and glutamatergic receptors in the dorsal striatum of the F1 offspring—this area of the brain is important for compulsivity and reward-seeking behavior.
“I wasn’t really expecting this significant of an effect,” Hurd says. “We thought that most of the epigenetic things that happened to you are erased, and basically you don’t pass on those epigenetics marks to your children.” Sperm and egg cells are believed to lose most of their acquired epigenetic marks during a “reprogramming” process when the two meet. “Now, we realize that that’s not true, so what are the mechanisms?”
Hurd’s lab is busy exploring this. Next, she plans to scour the epigenome of the pups, to see what their patterns of marks show. She also plans to see how this might play out in a second generation.
Other groups have found startling proof that past drug-taking behavior affects offspring. In January of 2013, Chris Pierce, a professor at the University of Pennsylvania Perelman School of Medicine, found that male offspring of rats who had been exposed to cocaine showed less addictive behavior toward cocaine. They then measured and found that levels of a certain protein, BDNF, were increased in the medial prefrontal cortex of the male pups.
Fair Vassoler, a co-author who was working in Pierce’s lab at the time, believes that this decreased susceptibility is not that surprising in that it is a protective effect. The study built on their earlier work that showed that in rats exposed to cocaine and then followed by a period of abstinence, levels of BDNF were increased in the prefrontal cortex, the decision-making center of the brain. BDNF, or brain-derived neurotrophic factor, is involved in the health of neurons, “a fertilizer of the brain,” Vassoler says. “This might be a compensatory mechanism,” in that in response to cocaine, the brain makes more BDNF “to prevent rats from taking more.” They hypothesize that the pups of cocaine-using rats have inherited the increased levels of BDNF to protect them from becoming addicts themselves. Females don’t share the protective effect, and Vassoler does not know why. Next steps are seeing how the next generation, F2, responds to cocaine, and if the protective effect is passed on to a third generation.
In a paper from late 2013, Vassoler, then working with Elizabeth Byrnes at Tufts University’s Cummings School of Veterinary Medicine, and her colleagues found that exposing adolescent female rats to cannabinoids enhanced their female pups’ response to morphine. In a most recent paper from April of this year, adolescent females exposed to morphine had male offspring who were more sensitive to morphine.
Considering rates of prescription opioid use and addiction—especially by younger people—Vassoler says the main take-home message of all this research is one of awareness. “Whether you’re male or female, [your behavior] can affect the next generation,” she says. “That’s pretty new, really important. And, it could really help to make people think before they act.”
IS THE DAMAGE REVERSIBLE?
The burning question on many recovering addicts’ minds will be, Is there anything I can do to reverse the damage I’ve done before having children? Most interviewed were cautioned about considering epigenetic changes as necessarily bad. And, many of these changes are transient—that is, methyl groups can be tagged on, and they can be tagged off—in response to environmental stimuli. Most importantly, these studies involve rodents; humans are much more complex in their response to stress.
“Some of these changes are reversible,” Harvard’s Sadri-Vakili says, while others are more static. A theory based on environmental enrichment has emerged which says that a stimulating, nurturing environment in recovery can help reverse these changes. Vassoler is a proponent – the last thing she wants is for recovering addicts to believe that they should not have babies. “The work that we’re doing in lab rats is so very far removed from humans,” who are obviously going to live a much more enriched life.
Sadri-Vakili emphasizes getting more exercise, or playing mentally stimulating games like chess, to increase levels of BDNF in the brain. “All these things will help boost BDNF levels,” she says, which is important for synaptic plasticity in improved learning and memory. “It keeps minds plastic, and growing, and healthy.”