Remember the first time you...? Mysterious brain structure sheds light on addiction

Cocaine-addicted mice shed light on claustrum's role in associating reward with context

July 23, 2020

Science Daily/The Hebrew University of Jerusalem

Do you remember where you were when you first heard that two planes had crashed into New York's Twin Towers? Or where you had your first kiss? Our brains are wired to retain information that relates to the context in which highly significant events occurred. This mechanism also underlies drug addiction and is the reason why hanging out in an environment or with people associated with memories of drug use often leads to relapse.

How our brains create this strong association, however, is less clear. Now, new research by Professor Ami Citri and PhD student Anna Terem at Hebrew University of Jerusalem (HU)'s Edmond and Lily Safra Center for Brain Sciences and the Alexander Silberman Institute of Life Science, shows that a relatively obscure brain region known as the claustrum plays a significant role in making these connections. They published their findings in the latest edition of Current Biology.

The researchers' findings fit the idea of "incentive salience," the process that determines the desirability of an otherwise neutral stimulus. For example, a candy store façade becomes very attractive to kids after repeated associations with the rewarding treats that lie within. In time, children unconsciously learn to "want" to see the store stimulus, which is separate from their "liking" the actual candy reward. Taking a closer look at how context becomes associated with cocaine, the researchers found a group of neurons within the claustrum that lit up during cocaine use. Further, these neurons are pivotal in the formation of an incentive salience that links context with the pleasure of cocaine.

To determine when and how the claustrum participates in incentive salience, Citri and his team employed a conditioned-place preference (CPP) test for a group of lab mice. During this test, the mice learned to associate reward with context. The researcher administered cocaine to the mice and placed them in an area with distinctive flooring (rugged) and wall patterns (dots), ones that a mouse would notice, as the drug started to kick in. After a few times of this, when placed in a room where the mice could choose either to hang out in a region similar to the one paired with cocaine (rugged floors and dots wall) or a neutral area (smooth floor and striped walls), the mice would quickly congregate in the area where their drug high had played out.

To test the claustrum's involvement in how a context becomes associated with a given reward, Citri and his team observed the changes in mice behavior when they inhibited these claustral neurons. They found that the inhibition of these neurons inhibited the mice's behavioral responses to cocaine, meaning they no longer preferred hanging out in the cocaine-paired environment. On the other hand, activating these neurons -- even in the absence of any cocaine -- caused the mice to develop a preference for this context.

Importantly, the team found that the activity of the claustrum was not necessary for retrieval of the cocaine memory. Once the mice had been placed in a cocaine-paired context several times to enjoy their cocaine high, the memory for this context was encoded and inhibition of the claustrum had no effect on their preference for the cocaine-paired context. "These findings boosted our confidence that the claustrum is indeed integral to incentive salience, heightening the awareness of the mouse to the context in which it experienced the drug high" shared Citri.

As the number of deaths caused by drug overdose increases from year to year, this new study has wide-ranging implications towards a better understanding of the nature of addiction and the importance of breaking contextual cues before they develop. "By recognizing that the claustrum plays a pivotal role in creating a context association for reward, it becomes a structure of interest for the field of addiction. We hope this knowledge will lead to the development of new diagnostic tools to identify populations susceptible to addiction, as well as new therapeutic approaches," concluded Terem.

https://www.sciencedaily.com/releases/2020/07/200723115904.htm

Prenatal cocaine exposure increases risk of higher teen drug use

May 3, 2017

Science Daily/Case Western Reserve University

While the crack cocaine epidemic peaked in the late 1980's, its effects are still causing harm to an estimated 3 million teenagers and young adults exposed to the stimulant in the womb.

They are twice as likely to use tobacco and marijuana at age 15 and develop a substance use disorder at 17 than teens who weren't exposed to the drug in utero, according to researchers at Case Western Reserve University.

They are also more likely to handle stress in negative ways, especially if mistreated as a child, using fewer problem-solving skills and having less control over their emotions. They're also more likely to become distracted or disengaged.

These poor coping strategies are typically associated with acting out behaviors: Teens in the study were likely to break rules, fight, show aggression, steal and use drugs, tobacco and alcohol.

At 15 years old, more than 36 percent of these teens had used a drug within the past month; at 17, it was 43 percent, significantly higher than their peers who were not exposed to cocaine in utero.

"Children exposed to cocaine in the womb are more susceptible to addiction themselves because they are more likely to have trouble controlling their behaviors and emotions, which can lead to using substances more often and at earlier ages," said Sonia Minnes, an associate professor at the Jack, Joseph and Morton Mandel School of Applied Social Sciences at Case Western Reserve.

As lead researcher of Project Newborn, a National Institutes of Health (NIH)-funded study that began in 1994, Minnes and her research team have followed babies with prenatal cocaine-exposure from birth into emerging adulthood.

While researchers are in the midst of a four-year, $2.5 million NIH grant to report on the group at age 21, the latest results come from two studies published in Drug and Alcohol Dependence that focus on the children at ages 15 and 17.

Cocaine, in any form, is toxic to a fetal brain, by restricting blood flow and altering the expression of genes, which can affect executive functioning, language and other types of development.

Many of the teens in the study were raised in chaotic caregiving environments; more than 30 percent reported maltreatment, including physical and emotional abuse and neglect.

These teens were more likely to use denial as a coping strategy and less likely to override initial impulses to calm themselves down, redirect thoughts positively or forego gratification when they also experienced childhood maltreatment.

"Prenatal cocaine exposure may predispose children to a lower threshold for activating 'stress circuits' and may increase their vulnerability to the harmful effects of environmental stress such as childhood maltreatment," said Meeyoung O. Min, a research associate professor at the Mandel School and a researcher with Project Newborn.

Many of the mothers in the study also used other substances during pregnancy including tobacco, alcohol and marijuana.

"Given the many challenges presented to these children, they are doing better than expected as they enter adulthood," Minnes said. "They are a testament to the benefits of providing a positive environment for a child who was put at higher risk due to drug exposure."

Project Newborn data suggests that specialized drug use prevention programs could benefit such high-risk children as they develop. In addition, the project's findings may provide insights into addressing similar public health crises, such as prenatal exposure to opiates.

"You want to prevent the next generation from using drugs while pregnant, and this is powerful data that helps make this case," Minnes said. "This project helps us better understand the many factors and pitfalls facing children whose mothers used drugs."

https://www.sciencedaily.com/releases/2017/05/170503080213.htm