Yasmin Hurd, director of the Mount Sinai Addiction Institute, deconstructed the neurobiology behind addiction disorders and presented new approaches for treatment of such diseases in a Thursday lecture at the Stanford Bio-X Clark Center Auditorium.

In the last few decades, drug abuse has become a major health concern in the United States, Hurd said. A record 70,000 people died of overdose in 2017. That number is higher than the amount of deaths from HIV, car crashes and gun violence at their respective peaks. However, addiction research does not receive the same attention as other fields in terms of funding.

“The United States is a drug country,” Hurd said. “Over 200 million opioid painkiller prescriptions are still written each year.”

Hurd, who is also the translational neuroscience chair at Mount Sinai’s Icahn School of Medicine, has examined neurochemical events in the human brain and in comparable animal model systems as she and her team aim to gain a molecular understanding of addiction in the human brain.

Hurd’s research topics include specific transcription factors, or proteins that control the rate of messenger RNA production from DNA. One such transcription factor, ELK1, could be involved in addiction caused by opioids, morphine, heroin and other drugs of abuse.

“ELK1 is a transcription factor targeting many of the genes that were altered [during addiction],” Hurd said. “It is strongly altered in heroin users, and changes the structure of the striatal cells [a region of the brain].”

In addition, Hurd found that the location of these transcription factors in the cell affected their behavior. For example, ELK1 in the nucleus of the cell will act differently from ELK1 in the cytoplasm of a cell. The “spines” of the neurons — small, membranous protrusions located on dendrites that typically receive signals from axons — will be formed differently based on the location of ELK1.

“We started on this track of studying post-mortem human brains,” Hurd said, reflecting back on her initial stages of research. “Now, we’re studying these [transcription factors] on a more biochemical level.”

Hurd also discussed how we can use what we know about the molecular neurobiology of addiction to develop clinical treatments.

Specifically, she explored the role of bromodomain and extra-terminal motif (BET) inhibitors, which are a promising class of drugs that reversibly bind to specific protein domains and are normally major targets in cancer research. Leveraging what has been discovered in the cancer research field, Hurd’s team is trying to identify similar BET compounds that can treat heroin abuse.

“The potential opportunity to translate the science that Dr. Hurd presented into fulfilling clinical unmet needs for people who are suffering from addiction disorders is what I found most interesting,” said Manpreet Singh, psychiatry and behavioral sciences associate professor at the Lucile Packard Children’s Hospital. “I have a greater appreciation for the molecular mechanisms that might be at play leading to increased vulnerabilities toward addiction.”

After highlighting other recent findings, including opioid receptor signaling pathways and other transcription factors that could be involved in the addiction pathology, Hurd discussed how animal behavioral studies can be used to learn more about human behavior.

Hurd’s animal research focuses on the decisions animals make when confronted with pieces of chocolate. One experiment involves placing a single piece of chocolate on two levers, and rigging another lever to give the animals five pieces of chocolate when pulled. The impulsivity test, she said, is to see if the animals will take short-term rewards over long-term rewards, even when the long-term rewards are inherently more enticing.

“Animals go for the five pieces of chocolate,” Hurd said. “But as we increase the time required to dispense five pieces, the more impulsive animals switch to the immediate [lever].”

Understanding the behavior of animals can lead to an understanding of human behavior as well, Hurd said. Testing impulsivity and motor control are prime examples of studies which can shed light on the correlation between animal and human behaviors.

Hurd also touched on increasing socio-political support of medical marijuana, a change she welcomes for its clinical implications, such as the possibility of using cannabidiol (CBD) — an active ingredient derived from the hemp plant — as a potential treatment option for opioid relapse.

“We are now carrying out a bigger trial [with CBD] because I do think it holds promise,” Hurd said.

 

Contact Tejas Athni at tathni ‘at’ stanford.edu.