December 1, 2017

The road to addiction recovery might become a little less rocky, thanks to a recent study by researchers at the Yerkes National Primate Research Center. Researchers suggest the drug fasudil, approved in Japan for cerebral vasospasm and stroke, could be an effective tool for treating drug abuse and preventing relapse.

Most of our everyday actions come from habits, not from deliberate decision-making. This can be detrimental in the case of drug abuse and drug-seeking behavior, says lead author Shannon Gourley, assistant professor of pediatrics, psychiatry and behavioral sciences at Emory University School of Medicine and Yerkes National Primate Research Center.

“Some habits are adaptive – for example, turning off a light when you exit a room – but others can be maladaptive, for example in the case of habitual drug use. We wanted to try to figure out a way to help ‘break’ habits, particularly those related to the highly addictive drug cocaine,” says Gourley.

She and former graduate students Andrew Swanson and Lauren Depoy first tested fasudil in situations where they had trained mice to poke their noses in two chambers, based on rewards of both food and cocaine. Then, the researchers changed the rules of the game – mice could now only get a reward from one chamber, instead of both. Fasudil helped the mice adjust and display “goal-directed” behavior, rather than their previous habit-based behavior.

Next, the researchers trained the mice to supply themselves a sweet cocaine solution. After the mice formed habit-based behavior, researchers changed the nature of that experience: the cocaine was paired with lithium chloride, making the mice feel sick. Fasudil treatment nudged the mice to give themselves less cocaine afterward, rather than continuing to respond habitually. Fasudil didn’t make cocaine itself less pleasurable, but was specifically modifying the habit process.

Unlearning habits involves remodeling connections made by cells in the brain. Fasudil seems to promote the pruning of dendritic spines, structures that help neurons communicate, by inhibiting Rho kinase, which helps stabilize cells’ internal skeletons. The drug thereby loosens the cell structures and appears to reduce the density of dendritic spines in the region of the brain important for learning new behaviors. Importantly, tests show fasudil must be directly paired with new learning to have that effect.

While overactive synaptic pruning has been proposed to play roles in Alzheimer’s disease and schizophrenia, when used appropriately, fasudil and similar compounds are promising candidates for drug addiction therapy.

 

Reviewed August 2019

January 22, 2016

An estimated 15.1 million adults in the United States have Alcohol Use Disorder (AUD), a chronic brain disease characterized by compulsive alcohol use. This includes approximately 6.2 percent of all American adults, a staggering percentage of drinkers nationwide.

“The amount of alcohol consumed in the US is not only substantial, but unequally divided in terms of who drinks how much,” said Dr. Kathleen Grant, Chief and Senior Scientist of Behavioral Neuroscience at the Oregon National Primate Research Center (ONPRC). “A small proportion drink the vast majority of alcohol sold.”

But why can some people safely enjoy a single nightcap, while others are at risk for developing alcoholism or a serious alcohol problem?

Dr. Grant hopes to answer that very question by studying a population of rhesus monkeys. Through her research, she is unraveling why some people are at a greater risk for heavy drinking habits.

Dr. Grant studies monkeys who have been exposed to alcohol over the course of three months. Like humans, some choose to drink water, some choose to drink alcohol, and some choose to drink a combination of the two. Understanding why certain monkeys choose to drink alcohol heavily provides clues as to why some humans are at a higher risk for developing a drinking problem.

Dr. Grant has found that males – both monkeys and humans – are more likely to become problem alcohol drinkers than females. In addition, monkeys that are exposed to stressful situations or stimuli choose to drink alcohol more than those that are not.

However, there are several risk factors that affect humans, but are not seen in monkeys. For example, in humans, family history of alcoholism can affect one’s inherited genes and environment and ultimately lead to an increased risk of heavy drinking. In addition, drinking alcohol between the ages of 13-15 increases the lifetime chances of being diagnosed with alcohol dependence.

Ultimately, Dr. Grant hopes her research will help identify those at risk for developing alcoholism before they’ve developed an alcohol addiction. By determining certain biomarkers in the brain and blood, she is hopeful that, eventually, we can caution people that they’re heading toward addiction before it begins.

“Prevention would be so much better for everyone because alcoholism affects more than just the individual,” Dr. Grant said.

Photo credit: Kathy West for the California National Primate Research Center

July 6, 2015

Kids can inherit their parents’ eye color, hair type, and even bone structure. But can genetics also explain a child’s anxiety levels? Researchers from the University of Wisconsin-Madison (UW) investigated whether there is a generational link for anxiety.

The study from UW’s Department of Psychiatry and the HealthEmotions Research Institute examined a large, multi-generational family of nearly 600 rhesus monkeys. Like humans, monkeys can become anxious when exposed to unfamiliar people, environment, or circumstances. In this study, monkeys were exposed to strangers who did not make eye contact – a situation that a human child may encounter.

During this situation, scientists used medical imaging methods commonly used on humans, including positron emission tomography (PET scans) exams, to identify the regions of the brain affected by anxiety. Once these medical images were taken, researchers compared brain activity within the rhesus family tree. The researchers found increased  activity across three parts of the brain 1) the amygdala, 2) the limbic brain fear center, and 3) the pre-frontal cortex.

“Over-activity of these three regions of the brain is directly linked to the later life risk to develop anxiety and depression,” said Dr. Ned Kalin, Wisconsin National Primate Research Center scientist and chair of psychiatry at the UW School of Medicine and Public Health. “This is a big step in understanding the neural underpinnings of inherited anxiety.”

This research marks a breakthrough in adolescent anxiety-related research, as it helps explain how genetics might affect brain function. Indeed, it was found that about 35% of anxiety tendencies can be explained by family history. Moreover, half of children who show extreme anxiety symptoms develop stress-related psychiatric disorders later in life.

“Now that we know where to look, we can develop a better understanding of the alterations that give rise to anxiety-related brain function,” Dr. Kalin said. “Our genes shape our brains to help make us who we are.”

 

Reviewed August 2019

November 13, 2013

According to the Centers for Disease Control and Prevention (CDC), more than 1 in 10 U.S. school-aged kids have received an Attention Deficit Hyperactivity Disorder, or ADHD, diagnosis. That’s 6.4 million children who struggle with inattentiveness, hyperactivity, and – as Dr. Luis Populin from the University of Wisconsin (UW) studies – impulsive behavior.

“If you say to an impulsive child, ‘Do your homework so you will get a good grade at the end of the quarter,’ that has less appeal than ‘Let’s play baseball this afternoon instead of studying chemistry,’” said Dr. Populin, an associate professor of neuroscience at UW-Madison.

To measure impulsive behavior, Dr. Populin studied rhesus monkeys at the Wisconsin National Primate Research Center who showed signs of ADHD, measuring the effects of methylphenidate (or Ritalin, a common ADHD drug) on their working memory and other aspects of executive functioning.

In the study, monkeys who exhibited calmer behavior learned to wait for a larger, delayed reward, while monkeys who tended to fidget and act nervously always chose the immediate, but smaller incentive. This willingness to take a small reward right away, rather than wait for the larger, delayed reward is called “temporal discounting.”

However, when given doses of methylphenidate, both monkeys chose the delayed reward more frequently, improving the condition of temporal discounting – but perhaps impacting other areas of the brain.

Armed with this information, Dr. Populin hopes to devise a mathematical tool that will help a doctor choose the correct dosage to reduce a child’s impulsive behavior – but not hinder executive function skills.

To continue his research, Dr. Populin was awarded the prestigious Hartwell Individual Biomedical Research Award, which provides research funding for three years. With this funding, Dr. Populin and his team are continuing their study of ADHD, examining kid’s temporal discounting (also known as delay discount and time discounting) while playing computer games.

“We will test temporal discounting with a game that kids don’t see as boring, but is still able to evaluate impulsivity so the doctor can make a faster, more accurate dosage calculations,” said Dr. Populin. “Then everybody benefits.”

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