Penn Study shows resistance to cocaine addiction may be passed down from father to son

Research from the Perelman School of Medicine at the University of Pennsylvania and Massachusetts General Hospital (MGH) reveals that sons of male rats exposed to cocaine are resistant to the rewarding effects of the drug, suggesting that cocaine-induced changes in physiology are passed down from father to son. The findings are published in the latest edition of Nature Neuroscience.

“We know that genetic factors contribute significantly to the risk of cocaine abuse, but the potential role of epigenetic influences – how the expression of certain genes related to addiction is controlled – is still relatively unknown,” said senior author R. Christopher Pierce, PhD, associate professor of Neuroscience in Psychiatry at Penn. “This study is the first to show that the chemical effects of cocaine use can be passed down to future generations to cause a resistance to addictive behavior, indicating that paternal exposure to toxins such as cocaine can have profound effects on gene expression and behavior in their offspring.”

In the current study, the team used an animal model to study inherited effects of cocaine abuse. Male rats self-administered cocaine for 60 days, while controls were administered saline. The male rats were mated with females that had never been exposed to the drug. To eliminate any influence that the males’ behavior would have on the pregnant females, they were separated directly after they mated.

The rats’ offspring were monitored to see whether they would begin to self-administer cocaine when it was offered to them. The researchers discovered that male offspring of rats exposed to the drug, but not the female offspring, acquired cocaine self-administration more slowly and had decreased levels of cocaine intake relative to controls. Moreover, control animals were willing to work significantly harder for a single cocaine dose than the offspring of cocaine-addicted rats, suggesting that the rewarding effect of cocaine was decreased.

In collaboration with Ghazaleh Sadri-Vakili, MS, PhD, from MGH, the researchers subsequently examined the animals’ brains and found that male offspring of the cocaine-addicted rats had increased levels of a protein in the prefrontal cortex called brain-derived neurotrophic factor (BDNF), which is known to blunt the behavioral effects of cocaine.

“We were quite surprised that the male offspring of sires that used cocaine didn’t like cocaine as much,” said Pierce. “While we identified one change in the brain that appears to underlie this cocaine resistance effect, there are undoubtedly other physiological changes as well and we are currently performing more broad experiments to identify them. We also are eager to perform similar studies with more widely used drugs of abuse such as nicotine and alcohol.”

Cocaine is a bitter, addictive pain blocker that is extracted from the leaves of Erythroxylon coca, also known as the coca scrub, a plant that comes from the Andean highlands in South America. Cocaine is the most powerful stimulant of natural origin. The name of “cocaine” came from the plant “coca”. When Coca-Cola first came out it contained nine milligrams of cocaine per glass - in 1903 it was removed, but the drink still has coca flavoring.

William S. Halstead (1852-1922), an American surgeon, injected cocaine into nerve trunks and demonstrated its numbing effect. It soon became used as an anesthetic agent. In 1898 August Bier, a German surgeon used cocaine as a spinal anesthetic. Not long afterwards the medical profession became aware of the addictive nature of cocaine and safer anesthetics were developed. Cocaine in its basic form stopped being used clinically as a pain blocker.


High risk of addiction
Animal laboratory studies have demonstrated how addictive cocaine can be. Animals will work much more persistently for a cocaine bar than any other drug, even opiates. Addicted humans eventually prefer taking cocaine to any other activity - their lifestyles may alter completely as the addiction takes hold more firmly. There have been cases of mothers selling their child, professionals spending thousands of dollars with binges costing from $20,000 to $50,000. Some may lose their jobs, families, become bankrupt, and even die.

Brain alterations - scientists at the University of Cambridge, England, identified abnormal brain structure in the frontal lobe of the brain of cocaine users that are associated with their cocaine-using behavior. They scanned the brains of 120 individuals, half of whom were addicted to cocaine. They found that the cocaine users had widespread loss of grey matter that was directly linked to how long they had been using cocaine - the longer the abuse, the greater the loss. They also found that those with the most reduction in volume had the greatest cocaine compulsivity.

They also found that the basal ganglia, the brain reward system where cocaine exerts its actions, was much larger among those dependent on cocaine. However, there was no association between the size of the enlargement and how long the person had been doing cocaine. The scientists believe that the enlargement may have occurred before cocaine usage, meaning that there are people who are more vulnerable to the effects of cocaine.

Exposure during teenage years - exposure to cocaine during adolescent years raises the “reinforcing effects” that make people vulnerable to developing an addiction, researchers from the University of Valencia, Spain found. The same was found with ecstasy. Adolescents who take cocaine often take ecstasy simultaneously - known as polyconsumption. According to studies carried out in Spain, 44% of cocaine users also take ecstasy, a practice that started off during adolescence.

Cocaine affects an epigenetic process - researchers at NIDA (National Institute on Drug Abuse, USA) identified a key epigenetic mechanism in the brain that helps explain cocaine’s addictiveness. Cocaine affected an epigenetic process - a process that can influence gene expression without altering a gene’s sequence - called histome methylation. These epigenetic alterations in the brain’s pleasure circuits, which appear to be the first affected by long-term cocaine exposure, are thought to contribute to an acquired preference for cocaine.

The findings suggest that cocaine use causes epigenetic changes in sperm, thereby reprogramming the information transmitted between generations. The researchers don’t know exactly why only the male offspring received the cocaine-resistant trait from their fathers, but speculate that sex hormones such as testosterone, estrogen and/or progesterone may play a role.


The first author of the paper, Fair M. Vassoler, PhD, is a recent graduate of the Penn neuroscience graduate group. Other investigators from Penn who contributed to this work include Samantha L. White and Heath D. Schmidt.

The work was supported by grants from the National Institutes of Health (R01 DA15214, R01 DA22339, R01 DA33641, K02 DA18678, K01 DA30445, F31 DA31535, T32 DA28874 and T32 MH86599).

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine is currently ranked #2 in U.S. News & World Report’s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $479.3 million awarded in the 2011 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania—recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital - the nation’s first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2011, Penn Medicine provided $854 million to benefit our community.


Jessica Mikulski
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University of Pennsylvania School of Medicine

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