Serotonin Receptors Can Shape Drug Effects from LSD to Migraine Medication

A team has determined and analyzed the high-resolution atomic structures of two kinds of human serotonin receptor, findings that shed light on several drugs' complex and sometimes harmful effects. 

Credit: Photo courtesy of The Scripps Research Institute.

A team including scientists from The Scripps Research Institute (TSRI), the University of North Carolina at Chapel Hill and the Chinese Academy of Sciences has determined and analyzed the high-resolution atomic structures of two kinds of human serotonin receptor.

The new findings help explain why some drugs that interact with these receptors have had unexpectedly complex and sometimes harmful effects.

"Understanding the structure-function of these receptors allows us to discover new biology of serotonin signaling and also gives us better ideas about what biological questions to probe in a more intelligent manner," said TSRI Professor Raymond Stevens, who was a senior investigator for the new research.

The studies were published in two papers on March 21, 2013 in Science Express, the advance online version of the journal Science.

Pioneering Important Molecular Structures
Stevens's laboratory at TSRI has pioneered the development of techniques for determining the 3D atomic structures of cellular receptors -- particularly the large receptor class known as G protein-coupled receptors (GPCRs).

GPCRs sit in the cell membrane and sense various molecules outside cells. When certain molecules bind to them, the receptor's respond in a way to transmit a signal inside the cell.

"Because G protein-coupled receptors are the targets of nearly 50 percent of medicines, they are the focus of several major National Institutes of Health (NIH) initiatives," said Jean Chin of the NIH's National Institute of General Medical Sciences, which partly funded the work through the Protein Structure Initiative.

"These detailed molecular structures of two serotonin receptor subfamilies bound to antimigraines, antipsychotics, antidepressants or appetite suppressants will help us understand how normal cellular signaling is affected by these drugs and will offer a valuable framework for designing safer and more effective medicines."

Serotonin receptors are no less important. "Nearly all psychiatric drugs affect serotonin receptors to some extent, and these receptors also mediate a host of effects outside the brain, for example on blood coagulation, smooth muscle contraction and heart valve growth," said Bryan Roth, a collaborator on both studies who is professor of pharmacology at the University of North Carolina (UNC).

Untangling Two Serotonin Receptors
Roth's laboratory teamed up with Stevens's as part of the National Institute of General Medical Sciences (NIGMS) Protein Structure Initiative.

For this project the two labs also worked with the laboratories of Professors Eric Xu and Hualiang Jiang at the Shanghai Institute of Materia Medica, part of the Chinese Academy of Sciences.

"By collaborating with the Chinese teams we were able to complete a much more thorough study and get the most out of our fundamental structural results," said Stevens.

In the first of the new studies, co-lead author Chong Wang, a graduate student in the Stevens laboratory, and his colleagues determined the structure of the serotonin receptor subtype 5-HT1B, the principal target of several drug classes. (5-HT, or 5-hydroxytryptamine, is a technical term for serotonin.)

The team produced the 5-HT1B receptor while it was bound by either ergotamine or dihydroergotamine -- two old-line anti-migraine drugs that work in part by activating 5-HT1B receptors.

With the help of the special fusion protein, nicknamed BRIL (apocytochrome b562RIL), Wang and colleagues were able to stabilize these structures and coax them to line up in a regular ordering known as a crystal.

X-ray crystallography revealed, at high resolution, an atomic structure of 5-HT1B with a main binding pocket and a separate, extended binding pocket.

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Depression Stems from Miscommunication Between Brain Cells; Study Challenges Role of Serotonin in Depression

A new study from the University of Maryland School of Medicine suggests that depression results from a disturbance in the ability of brain cells to communicate with each other. 

Credit: © Artur Golbert / Fotolia

A new study from the University of Maryland School of Medicine suggests that depression results from a disturbance in the ability of brain cells to communicate with each other.

The study indicates a major shift in our understanding of how depression is caused and how it should be treated. Instead of focusing on the levels of hormone-like chemicals in the brain, such as serotonin, the scientists found that the transmission of excitatory signals between cells becomes abnormal in depression.

Scott M. Thompson

The research, by senior author Scott M. Thompson, Ph.D., Professor and Interim Chair of the Department of Physiology at the University of Maryland School of Medicine, was published online in the March 17 issue of Nature Neuroscience.

According to the Centers for Disease Control and Prevention, between 2005 and 2008, approximately one in 10 Americans were treated for depression, with women more than twice as likely as men to become depressed.

The most common antidepressant medications, such as Prozac (Fluoxetine), Zoloft (Setraline) and Celexa (Citalopram), work by preventing brain cells from absorbing serotonin, resulting in an increase in its concentration in the brain.

Unfortunately, these medications are effective in only about half of patients. Because elevation of serotonin makes some depressed patients feel better, it has been thought for over 50 years that the cause of depression must therefore be an insufficient level of serotonin.

The new University of Maryland study challenges that long-standing explanation.

"Dr. Thompson's groundbreaking research could alter the field of psychiatric medicine, changing how we understand the crippling public health problem of depression and other mental illness," says E. Albert Reece, M.D., Ph.D., M.B.A., Vice President for Medical Affairs at the University of Maryland and John Z. and Akiko K. Bowers Distinguished Professor and Dean at the University of Maryland School of Medicine.

"This is the type of cutting-edge science that we strive toward at the University of Maryland, where discoveries made in the laboratory can impact the clinical practice of medicine."

Depression affects more than a quarter of all U.S. adults at some point in their lives, and the World Health Organization (WHO) predicts that by 2020 it will be the second leading cause of disability worldwide.

Depression is also the leading risk factor for suicide, which causes twice as many deaths as murder, and is the third leading cause of death for 15-24 year olds.

The first major finding of the study was the discovery that serotonin has a previously unknown ability to strengthen the communication between brain cells.

"Like speaking louder to your companion at a noisy cocktail party, serotonin amplifies excitatory interactions in brain regions important for emotional and cognitive function and apparently helps to make sure that crucial conversations between neurons get heard," says Dr. Thompson.

"Then we asked, does this action of serotonin play any role in the therapeutic action of drugs like Prozac?"

To understand what might be wrong in the brains of patients with depression and how elevating serotonin might relieve their symptoms, the study team examined the brains of rats and mice that had been repeatedly exposed to various mildly stressful conditions, comparable to the types of psychological stressors that can trigger depression in people.

The researchers could tell that their animals became depressed because they lost their preference for things that are normally pleasurable.

For example, normal animals given a choice of drinking plain water or sugar water strongly prefer the sugary solution. Study animals exposed to repeated stress, however, lost their preference for the sugar water, indicating that they no longer found it rewarding.

This depression-like behaviour strongly mimics one hallmark of human depression, called anhedonia, in which patients no longer feel rewarded by the pleasures of a nice meal or a good movie, the love of their friends and family, and countless other daily interactions.

A comparison of the activity of the animals' brain cells in normal and stressed rats revealed that stress had no effect on the levels of serotonin in the 'depressed' brains.

Instead, it was the excitatory connections that responded to serotonin in strikingly different manner. These changes could be reversed by treating the stressed animals with antidepressants until their normal behaviour was restored.

"In the depressed brain, serotonin appears to be trying hard to amplify that cocktail party conversation, but the message still doesn't get through," says Dr. Thompson.

Using specially engineered mice created by collaborators at Johns Hopkins University School of Medicine, the study also revealed that the ability of serotonin to strengthen excitatory connections was required for drugs like antidepressants to work.

Sustained enhancement of communication between brain cells is considered one of the major processes underlying memory and learning.

The team's observations that excitatory brain cell function is altered in models of depression could explain why people with depression often have difficulty concentrating, remembering details, or making decisions.

Additionally, the findings suggest that the search for new and better antidepressant compounds should be shifted from drugs that elevate serotonin to drugs that strengthen excitatory connections.

"Although more work is needed, we believe that a malfunction of excitatory connections is fundamental to the origins of depression and that restoring normal communication in the brain, something that serotonin apparently does in successfully treated patients, is critical to relieving the symptoms of this devastating disease," Dr. Thompson explains.

The above story is reprinted from materials provided by University of Maryland Medical Center.

Childhood Bullying Has Long term Effects: Mood Disorders

Bullying by peers changes the structure surrounding a gene involved in regulating mood, making victims more vulnerable to mental health problems as they age.

This is the reported finding of a recent study by a researcher at the Centre for Studies on Human Stress (CSHS) at the Hôpital Louis-H. Lafontaine and professor at the Université de Montréal suggests that .

The study published in the journal Psychological Medicine seeks to better understand the mechanisms that explain how difficult experiences disrupt our response to stressful situations.

"Many people think that our genes are immutable; however this study suggests that environment, even the social environment, can affect their functioning. This is particularly the case for victimization experiences in childhood, which change not only our stress response but also the functioning of genes involved in mood regulation," says Isabelle Ouellet-Morin, lead author of the study.

A previous study by Ouellet-Morin, conducted at the Institute of Psychiatry in London (UK), showed that bullied children secrete less cortisol -- the stress hormone -- but had more problems with social interaction and aggressive behaviour.

The present study indicates that the reduction of cortisol, which occurs around the age of 12, is preceded two years earlier by a change in the structure surrounding a gene (SERT) that regulates or transports serotonin, and is a neurotransmitter involved in mood regulation and depression.

To achieve these results, 28 pairs of identical twins with a mean age of 10 years were analyzed separately according to their experiences of bullying by peers: one twin had been bullied at school while the other had not.

"Since they were identical twins living in the same conditions, changes in the chemical structure surrounding the gene cannot be explained by genetics or family environment. Our results suggest that victimization experiences are the source of these changes," says Ouellet-Morin.

According to the author, it would now be worthwhile to evaluate the possibility of reversing these psychological effects, in particular, through interventions at school and support for victims.

Serotonin Levels: Protein in overdrive links to Autism (ASD)

Early disruptions in serotonin signaling in the brain may contribute to Autism Spectrum Disorder (ASD) and other “enduring effects on behavior,” researchers report.

Serotonin is a brain chemical that carries signals across the synapse, or gap between nerve cells. The supply of serotonin is regulated by the serotonin transporter (SERT).

In 2005, a team of researchers from Vanderbilt University led by Randy Blakely and James Sutcliffe identified rare genetic variations in children with ASD that disrupt SERT function.

In a new study published this week in the Proceedings of the National Academy of Sciences (PNAS), the researchers report the creation of a mouse model that expressed the most common of these variations.

The change is a very small one in biochemical terms, yet it appears to cause SERT in the brain to go into “overdrive” and restrict the availability of serotonin at synapses.

“The SERT protein in the brain of our mice appears to exhibit the exaggerated function and lack of regulation we saw using cell models,” says Blakely, director of the Vanderbilt Silvio O. Conte Center for Neuroscience Research.

“Remarkably, these mice show changes in social behavior and communication from early life that may parallel aspects of ASD,” notes first author Jeremy Veenstra-VanderWeele, assistant professor of psychiatry, pediatrics and pharmacology.

The researchers conclude that a lack of serotonin during development may lead to long-standing changes in the way the brain is “wired.”

In 1961, investigators at Yale University discovered that as many as 30 percent of children with autism have elevated blood levels of serotonin, a finding described as “hyperserotonemia.”

Since then, these findings have been replicated many times. Indeed, hyperserotonemia is the most consistently reported biochemical finding in autism, and is a highly inherited trait. Yet, the cause or significance of this biomarker has remained shrouded in mystery.

Until now. In the current study, Veenstra-VanderWeele, Blakely and their colleagues showed that they could produce hyperserotonemia in mice that express a variant of a human SERT gene associated with autism.

Because the genetic change makes the transporter more active, higher levels of serotonin accumulate in platelets and therefore in the bloodstream.

In the brain, overactive transporters should have the opposite effect—lowering serotonin levels at the synapse and producing behavioural changes relevant to autism. That’s exactly what the researchers observed.

Of course, no mouse model can completely explain or reproduce the human condition. Neither does a single genetic variation cause autism. Experts believe the wide spectrum of autistic behaviours represents a complex web of interactions between many genes and environmental factors.

But animal models are critical to exploring more deeply the basis for the developmental changes that are observed in ASD.

The scientists are using these mice to explore how altered brain serotonin levels during development may produce long-lasting changes in behaviour and impact the risk for autism.

Scientists from the National Institute of Mental Health, the Medical University of South Carolina and the University of Texas Health Science Center in San Antonio contributed to the study.

The research was supported by the National Institutes of Health, the advocacy organisation Autism Speaks (UK), and the American Academy of Child and Adolescent Psychiatry.

More news from Vanderbilt University: news.vanderbilt.edu/research