A History of Cocaine and Possible Epigenetic Effects of the Drug

To kick off the Psychology and Neuroscience Lecture Series for the Fall 2011 semester, Associate Professor of Neuroscience Chris Pierce from the University of Pennsylvania School of Medicine visited Goodpaster Hall on Sept. 19 to discuss his neurobiological cocaine addiction research in his lecture, “Epigenetic Inheritance of a Cocaine Resistance Phenotype.”

Pierce began his lecture by giving a brief history of the origins of cocaine, explaining how it went from an Incan pharmacological drug to the dangerously addictive drug that it is known to be today. One of the first popular uses of cocaine was to put it into a tea, called “mate de coca.”

“It really tasted bad, it’s very bitter… It’s basically like caffeine,” said Pierce.

Cocaine can also be chewed, in the form of coca leaves. This is very popular amongst miners in Peru. “What these miners do is they basically get to work and they start chewing coca leaves. It’s a very inefficient way to get cocaine into the system. Saliva is not very good at breaking it down. They have to chew it all day. It takes about five to six hours,” said Pierce, “But, they’ll finally get a jolt in the middle of the afternoon and it helps them power through the rest of the day.”

The first person to isolate cocaine was Albert Neiman in 1860. At that time, he was the only person who had access to purified cocaine. Coincidentally, Neiman died due to mysterious circumstances in 1861. After that, drug companies began mass-producing cocaine.

Psychoanalyst Sigmund Freud wrote his first scientific publication on the benefits of cocaine. Freud “thought cocaine was great, [he] saw no downsides to [it] at all. He named a dozen ailments that he thought cocaine treated,” said Pierce. For example, Freud claimed that cocaine could cure depression, alcoholism, morphine addictions, and also act as a local anesthetic. He began producing copious quantities of the drug himself and people throughout Europe and America began prescribing it. This caused a huge wave of cocaine addictions. People can now point at Freud and say, “You caused a pandemic of addiction,” said Pierce. Freud was, however, right about the anesthetic properties of cocaine. It soon became the first local anesthetic to be itemized.

Not long afterwards, Angelo Mariani had the idea of combining cocaine with wine, which was very dangerous. He wanted to recruit people to write testimonies on the drink, so he sent a bottle of the wine to the 1,000 most famous people on the planet. People like President William McKinley, H.G. Wells, and Thomas Eddison wrote praising testimonials in return. Mariani even received a gold medal for the medical benefits of cocaine from Pope Leo XIII.

Vin Mariani led directly to the later production of Coca Cola by John Pemberton, which originally contained real coca leaves. Alcohol prohibition in Atlanta forced people to get creative with their vices, so Pemberton decided to replace the alcohol in Vin Mariani with carbonated water, but kept the coca leaves. Cocaine was later outlawed in 1918, and the ingredients in Coca Cola had to be changed. One drug company in southern New Jersey is still allowed to produce cocaine for medical purposes.

Pierce has looked into the current state of cocaine use across the nation and the reasons why many cocaine users, after going through rehabilitation, tend to relapse. “Merely seeing the paraphernalia that’s related to cocaine can lead to craving and relapse,” said Pierce.

Pierce was curious about the genetic properties of cocaine and how children of parents who were or are addicted to cocaine could react to the drug differently in their own life. To study this, Pierce had male rats become addicted to cocaine and mate with a non-addicted female. Then, he researched how the next generation of rats would react to cocaine.

Previous research showed that after fourteen days of cocaine self-administration (having a rat press a lever in a cage to receive cocaine dosages), the animals started showing increased transcription of brain-derived neurotropic factor (BDNF). In short, these results meant that cocaine was potentially having an effect at the genetic level.

Further genetic analysis indicated that cocaine self-administration caused increased transcription of BDNF messenger ribonucleic acid (mRNA), a genetic precursor of BDNF, in the prefrontal cortex (PFC). More specifically, cocaine caused increased transcription of exon four of the BDNF gene, one of the building blocks of the BDNF protein code, by causing three effects.

The drug not only increased acetylation of exon four (which “opened up” the gene for increased expression), but it also increased levels of CREB and decreased levels of MeCP2 in the PFC. Given that CREB is a transcription factor that increased expression of BDNF and MeCP2 decreases BDNF expression, increasing the former and decreasing the latter caused increased production of BDNF.

After having discovered that cocaine has an effect on BDNF expression, Pierce next tested the effect of decreasing BDNF in the prefrontal cortex on cocaine efficacy. After administering BDNF shRNA, which decreased expression of BDNF in the prefrontal cortex by 60%, the rats showed more readiness to press a lever over 200 times for cocaine administration, showing an enhanced reinforcing efficacy of cocaine. This meant that when cocaine causes increased BDNF expression in the rat prefrontal cortex, cocaine efficacy decreases, and the rats become less interested in cocaine.

“Ultimately, humans and animals become addicted,” said Pierce, “…[but] your prefrontal cortex is saying don’t take cocaine.”

However, these effects are not targeting the genetic sequence itself, but its regulation. Pierce then investigated whether this non-sequence effect would be inheritable by future offspring, also known as an epigenetic effect. To begin this study, Pierce studied the offspring of two rats, a male treated with cocaine for 60 days (ensuring all of the sperm were exposed to cocaine) and a female treated with saline (no cocaine effect). He found that while the female offspring (F1 females) showed no change in cocaine addiction, male rats (F1 males) showed decreased reinforcement of cocaine, similar to the effect of increasing PFC BDNF in cocaine-exposed rats.

According to Pierce, a concern with proving this result as an epigenetic effect is not having data for another generation of rats, the offspring of the mice sired by the male rat exposed to cocaine for 60 days (F2 males and females). If the effect is inheritable, the next generation should show the same effect as the F1 male rats, even without the F1 males being exposed to cocaine. This seemed to be a point of concern with several members of the audience, as data on this generation would confirm this effect as epigenetic.

“I enjoyed the presentation. Epigenetics is a concept extending across many fields. One day we will completely understand the mechanisms behind it, which will allow us to regulate its effects,” said senior Luke Trout.

“I thought that Dr. Pierce did a very entertaining presentation,” said senior Jesse Burke. “I like how he started out with the history of cocaine and slowly transitioned into how cocaine has made its way into today’s society. He also proposed the idea of epigenetics, something I have never really heard of before this presentation.”

The next Psychology and Neuroscience Lecture, “The Neurology of Concussion” by Kevin Crutchfield, ’83, will be on Sept. 30 at 3:00 p.m. in Goodpaster 195.

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