Tag: serotonin

Categories : Diet and Nutrition Mental HealthTags :

High-fat Diets can Interfere with Serotonin Pathways, Fuelling Anxiety

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Photo by Jonathan Borba

New research from CU Boulder shows that turning to junk food when we’re stressed out may backfire. The study found that in animals, a high-fat diet disrupts resident gut bacteria, alters behaviour and, through a complex pathway connecting the gut to the brain, influences brain chemicals in ways that fuel anxiety.

“Everyone knows that these are not healthy foods, but we tend to think about them strictly in terms of a little weight gain,” said lead author Christopher Lowry, a professor of integrative physiology at CU Boulder. “If you understand that they also impact your brain in a way that can promote anxiety, that makes the stakes even higher.”

For the study, published in the journal Biological Research in May, Lowry worked with first author Sylvana Rendeiro de Noronha, a doctoral student at the Federal University of Ouro Preto in Brazil.

In a previous study, the team found that rats fed a high-fat diet consisting primarily of saturated fat showed increases in neuroinflammation and anxiety-like behaviour.

While evidence is mixed, some human studies have also shown that replacing a high-fat, high-sugar, ultra-processed diet with a healthier one can reduce depression and anxiety.

The dark side of serotonin

To better understand what may be driving the fat-anxiety connection, Lowry’s team divided male adolescent rats into two groups: Half got a standard diet of about 11% fat for nine weeks; the others got a high-fat diet of 45% fat, consisting mostly of saturated fat from animal products.

The typical American diet is about 36% fat, according to the Centers for Disease Control and Prevention.

Throughout the study, the researchers collected faecal samples and assessed the animals’ gut microbiome. After nine weeks, the animals underwent behavioural tests.

When compared to the control group, the group eating a high-fat diet, not surprisingly, gained weight. But the animals also showed significantly less diversity of gut bacteria. Generally speaking, more bacterial diversity is associated with better health, Lowry explained. They also hosted far more of a category of bacteria called Firmicutes and less of a category called Bacteroidetes. A higher Firmicutes to Bacteroidetes ratio has been associated with the typical industrialised diet and with obesity.

The high-fat diet group also showed higher expression of three genes (tph2, htr1a, and slc6a4) involved in production and signalling of the neurotransmitter serotonin – particularly in a region of the brainstem known as the dorsal raphe nucleus cDRD, which is associated with stress and anxiety.

While serotonin is often billed as a “feel-good brain chemical,” Lowry notes that certain subsets of serotonin neurons can, when activated, prompt anxiety-like responses in animals. Notably, heightened expression of tph2, or tryptophan hydroxylase, in the cDRD has been associated with mood disorders and suicide risk in humans.

“To think that just a high-fat diet could alter expression of these genes in the brain is extraordinary,” said Lowry. “The high-fat group essentially had the molecular signature of a high anxiety state in their brain.”

A primal gut-brain connection

Just how a disrupted gut can change chemicals in the brain remains unclear. But Lowry suspects that an unhealthy microbiome compromises the gut lining, enabling bacteria to slip into the body’s circulation and communicate with the brain via the vagus nerve, a pathway from the gastrointestinal tract to the brain.

“If you think about human evolution, it makes sense,” Lowry said.  “We are hard-wired to really notice things that make us sick so we can avoid those things in the future.”

Lowry stresses that not all fats are bad, and that healthy fats like those found in fish, olive oil, nuts and seeds can be anti-inflammatory and good for the brain.

But his research in animals suggests that exposure to an ultra-high-fat diet consisting of predominantly saturated fats, particularly at a young age, could both boost anxiety in the short-term and prime the brain to be more prone to it in the future.

His advice: Eat as many different kinds of fruits and vegetables as possible, add fermented foods to your diet to support a healthy microbiome and lay off the pizza and fries. Also, if you do have a hamburger, add a slice of avocado. Research shows that good fat can counteract some of the bad.

Rodrigo Cunha de Menezes, professor of physiology at Federal University of Ouro Preto in Brazil, is co- senior author on this paper.

Source: University of Colorado Boulder

Categories : Mental Health Obstetrics & GynaecologyTags :

Antidepressants Impact Prefrontal Cortex Development

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Photo by William Fortunato on Pexels

A new study published in Nature Communications suggests that use of antidepressants can impact early post-natal brain development, potentially contributing to the development of mental health disorders. The study, led by researchers at the University of Colorado Anschutz Medical Campus, focused on the effect of fluoxetine, commonly used in medications such as Prozac and Sarafem for treating depression and perinatal depression, on the developing prefrontal cortex of mice.

Since fluoxetine works by increasing the levels of serotonin in the brain, the researchers looked at the impact serotonin has on prefrontal cortex development.

“While it is known that serotonin plays a role in the brain development, the mechanisms responsible for this influence, specifically in the prefrontal cortex, have been unclear, ” said lead author Won Chan Oh, PhD, assistant professor in the Department of Pharmacology at CU Anschutz.

Changes in gestational and early postnatal serotonin levels can arise from many causes including maternal deprivation or abuse, diets high or low in tryptophan, or the use of medications such as selective serotonin reuptake inhibitors (SSRIs) that can readily cross the placenta or be passed to offspring through breast feeding. Disbalances of 5-HT during brain development are associated with increased risk of neurodevelopmental disorders such as autism spectrum disorder and long-lasting behavioural deficits, but the underlying mechanisms remain elusive.

Oh and his student, Roberto Ogelman, a neuroscience PhD candidate, found serotonin directly influences nascent and immature excitatory synaptic connections in the prefrontal cortex, which if disrupted or dysregulated during early development can contribute to various mental health disorders.

“Our research uncovers the specific processes at the synaptic level that explain how serotonin contributes to the development of this important brain region during early-life fluoxetine exposure,” adds Oh. “We are the first to provide experimental evidence of the direct impact of serotonin on the developing prefrontal cortex in mice.”

To study the effect, the researchers looked at the impact of deficiency and surplus of serotonin on brain development in mice. They discovered that serotonin is not just involved in overall brain function but also has a specific role in influencing how individual connections between neurons change and adapt, contributing to the brain’s ability to learn and adjust.

“Understanding this correlation has the potential to help with early intervention and the development of new therapeutics for neurodevelopmental disorders involving serotonin dysregulation,” said Oh.

The researchers plan to continue studying the impact of fluoxetine, next examining its impact on a developing brain later in life.

Source: Colorado University Anschutz Medical Campus

Categories : Cardiovascular DiseaseTags :

Serotonin Link Found in Degenerative Mitral Regurgitation

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Anatomical model of a human heart
Photo by Robina Weermeijer on Unsplash

Serotonin can impact the mitral valve of the heart and potentially accelerate a cardiac condition known as degenerative mitral regurgitation, according to a new study published in Science Translational Medicine.

Degenerative mitral regurgitation

Degenerative mitral regurgitation (DMR) is one of the most common heart valve diseases. The mitral valve is located between the left atrium and left ventricle of the heart, and normally it closes tightly when the heart contracts to prevent blood from leaking back into the left atrium.

In DMR, the mitral valve shape is distorted, preventing complete closure. This allows blood to leak back toward the lungs (regurgitation), limiting the amount of oxygen-rich blood moving through the heart to the rest of the body.

As a result, DMR can bring about symptoms like fatigue and shortness of breath. Because of the reduced efficiency in circulation, the heart has to work harder, which over time causes permanent damage. This can lead to a number of serious and life-threatening cardiac issues, including atrial fibrillation and heart failure.

Currently, there is no treatment for mitral valve degeneration. “Certain medications can ease the symptoms and prevent complications, but they do not treat the mitral valve,” says co-lead researcher, Columbia University’s Giovanni Ferrari, PhD. “If the degeneration of the mitral valve becomes severe, surgery to repair or replace the valve is needed.”

The role of serotonin

Serotonin plays a part in a wide range of body functions, including emotional state, digestion, sleep, memory, and blood-clotting. Serotonin’s role as a neurotransmitter aids mood regulation; lower levels of serotonin are associated with anxiety and depression.

Serotonin binds to specific receptors on the surface of a cell, sending a signal to the cell to act accordingly. A protein known as the serotonin transporter (SERT or 5-HTT) moves serotonin into the cell to be reabsorbed and recycled, a process known as serotonin reuptake.

Medications called selective serotonin reuptake inhibitors (SSRIs) bind to the SERT to reduce serotonin reuptake, allowing serotonin to remain available for longer periods. This increased serotonin availability can help improve symptoms of mood disorders. SSRIs are some of the most widely prescribed types of antidepressants and include well-known medications like fluoxetine (Prozac) and sertraline (Zoloft).

Study design

The study examined clinical data from more than 9000 patients who had undergone valve repair or replacement surgery for DMR and evaluated 100 mitral valve biopsies. “Studying the data of these patients, we found that taking SSRIs was associated with severe mitral regurgitation that needed to be treated with surgery at a younger age than for patients not taking SSRIs,” says Ferrari.

The researchers also studied in vivo mouse models using transgenic mice lacking the SERT gene and normal mice. They discovered that mice without a SERT gene developed thicker mitral valves and that normal mice treated with high doses of SSRIs also developed thickened mitral valves.

Using genetic analysis, the researchers identified genetic variants in the SERT gene region 5-HTTLPR that affect SERT activity. They found that a “long” variant of 5-HTTLPR makes SERT less active in the mitral valve cells, especially when there are two copies (one maternal and one paternal). DMR patients with the “long-long” variant needed mitral valve surgery more often than those with other variants.

Mitral valve cells from DMR patients with the “long-long” variant were more prone to react to serotonin by producing more collagen, changing the shape of the mitral valve. Additionally, mitral valve cells with the “long-long” variant of 5-HTTLPR were more sensitive to fluoxetine than those with other variants.

Implications for MVD patients

The study indicates that for DMR patients with the “long-long” variant, taking SSRIs lowers SERT activity in the mitral valve. The researchers suggest testing DMR patients for potential low SERT activity by genotyping them for 5-HTTLPR, which can be determined easily from a DNA sample obtained from the blood or a mouth swab. “Assessing patients with DMR for low SERT activity may help identify patients who may need mitral valve surgery earlier,” says Ferrari. “Promptly fixing a mitral valve that is very leaky would protect the heart and could prevent congestive heart failure.”

The researchers did not find a negative effect with normal doses of SSRIs or the “long-long” variant in cells from healthy human mitral valves. “A healthy mitral valve can probably stand low SERT activity without deforming,” says Ferrari. “It is unlikely that low SERT can cause degeneration of the mitral valve by itself. SSRIs are generally safe for most patients. Once the mitral valve has started to degenerate, it may be more susceptible to serotonin and low SERT.”

Additional research may help determine if DMR patients who respond well to SSRIs should be regularly seen to assess progression of mitral degeneration, and whether DMR patients who are not responding well to SSRIs should consider switching to a non-SSRI antidepressant rather than raising the dose of the SSRI.

Source: Columbia University Irving Medical Center

Categories : Medical Research & Technology Mental HealthTags :

No Evidence that Serotonin Imbalance Causes Depression

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Depression, young man
Source: Andrew Neel on Unsplash

Decades of research has provided no clear evidence that serotonin levels or serotonin activity are responsible for depression, according to a major review of existing literature.

Published in Molecular Psychiatry, this new umbrella review is an overview of existing meta-analyses and systematic reviews. It suggests that depression is not likely to be caused by a chemical imbalance. It also calls into question what antidepressants do: most antidepressants are selective serotonin reuptake inhibitors (SSRIs), whose mechanism of action was supposedly to correct abnormally low serotonin levels. But there is no other accepted pharmacological mechanism by which antidepressants affect the symptoms of depression.

Lead author Professor Joanna Moncrieff, at University College London said: “It is always difficult to prove a negative, but I think we can safely say that after a vast amount of research conducted over several decades, there is no convincing evidence that depression is caused by serotonin abnormalities, particularly by lower levels or reduced activity of serotonin.

“The popularity of the ‘chemical imbalance’ theory of depression has coincided with a huge increase in the use of antidepressants. Prescriptions for antidepressants have risen dramatically since the 1990s, with one in six adults in England and 2% of teenagers now being prescribed an antidepressant in a given year.

“Many people take antidepressants because they have been led to believe their depression has a biochemical cause, but this new research suggests this belief is not grounded in evidence.”

The umbrella review aimed to capture all relevant studies, encompassing tens of thousands of participants, that have been published in the most important fields of research on serotonin and depression.

Research that compared levels of serotonin and its breakdown products in the blood or brain fluids found no difference between participants diagnosed with depression and healthy controls.

Research on serotonin receptors and the serotonin transporter, the protein targeted by most antidepressants, found weak and inconsistent evidence suggestive of higher levels of serotonin activity in people with depression. However, the researchers say the findings are likely explained by the use of antidepressants among people diagnosed with depression, since such effects were not reliably ruled out.

Some studies artificially lowered serotonin levels were by depriving participant’s diets of the necessary amino acid. These studies have been cited as demonstrating that a serotonin deficiency is linked to depression. A meta-analysis conducted in 2007 and a sample of recent studies found that lowering serotonin in this way did not produce depression in hundreds of healthy volunteers, however. There was very weak evidence in a small subgroup of people with a family history of depression, but this only involved 75 participants, and more recent evidence was inconclusive.

Very large studies involving tens of thousands of patients looked at gene variation, including the gene for the serotonin transporter, and found no difference between people with depression and healthy controls. These studies also examined stressful life events, and found these to strongly increase people’s risk of becoming depressed. A famous early study found a relationship between stressful events, the type of serotonin transporter gene a person had and the chance of depression. But larger, more comprehensive studies suggest this was a false finding.

These findings together led the authors to conclude that there is “no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.”

The researchers say their findings are important as studies show that as many as 85–90% of the public believes that depression is caused by low serotonin or a chemical imbalance. A growing number of scientists and professional bodies are recognising the chemical imbalance framing as an over-simplification. Evidence also suggests that believing that low mood is caused by a chemical imbalance leads to pessimism about recovery, and the possibility of managing moods without medical help. This is important because most people will at some point in their lives meet criteria for anxiety or depression.

A large meta-analysis provided evidence that people who used antidepressants actually had lower levels of serotonin in their blood. The researchers concluded that some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentrations. The researchers say this may imply that the increase in serotonin that some antidepressants produce in the short term could lead to compensatory changes in the brain that produce the opposite effect in the long term.

Though antidepressants’ efficacies was not examined, the authors encourage looking into treatments such psychotherapy, alongside other practices such as exercise or mindfulness, or addressing underlying contributors such as poverty, stress and loneliness.

Professor Moncrieff said: “Our view is that patients should not be told that depression is caused by low serotonin or by a chemical imbalance, and they should not be led to believe that antidepressants work by targeting these unproven abnormalities. We do not understand what antidepressants are doing to the brain exactly, and giving people this sort of misinformation prevents them from making an informed decision about whether to take antidepressants or not.”

Co-author Dr Mark Horowitz said: “I had been taught that depression was caused by low serotonin in my psychiatry training and had even taught this to students in my own lectures. Being involved in this research was eye-opening and feels like everything I thought I knew has been flipped upside down.

“One interesting aspect in the studies we examined was how strong an effect adverse life events played in depression, suggesting low mood is a response to people’s lives and cannot be boiled down to a simple chemical equation.”

Professor Moncrieff added: “Thousands of people suffer from side effects of antidepressants, including the severe withdrawal effects that can occur when people try to stop them, yet prescription rates continue to rise. We believe this situation has been driven partly by the false belief that depression is due to a chemical imbalance. It is high time to inform the public that this belief is not grounded in science.”  

Source: EurekAlert!

Categories : Mental Health Metabolic DisordersTags :

Migraine Drug Could be Beneficial for Weight Loss

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Obesity
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The commonly prescribed triptans, a class of migraine drugs, may be useful in treating obesity, a new study published in Journal of Experimental Medicine suggests. In studies on obese mice, a daily dose of a triptan caused them to eat less food and lose weight over the course of a month.

“We’ve shown that there is real potential to repurpose these drugs, which are already known to be safe, for appetite suppression and weight loss,” said study leader Chen Liu, PhD.

Serotonin has long been known to play a key role in appetite. However, there are 15 different serotonin receptors. Researchers have struggled to understand the role of each serotonin receptor in appetite, and previous drugs, including fen-phen and lorcaserin, that targeted certain individual receptors have been withdrawn from the market due to side effects.

Triptans, which are used to treat acute migraines and cluster headaches, work by targeting a different receptor — the serotonin 1B receptor (Htr1b) — that had not previously been well studied in the context of appetite and weight loss, said Dr Liu.

For the new study, the researchers tested six prescription triptans in obese mice that were fed a high-fat diet for seven weeks. Mice fed two of these drugs ate about the same amount, but mice fed the other four ate less. After 24 days, mice given a daily dose of the drug frovatriptan lost, on average, 3.6% of their body weight, while mice not given a triptan gained an average of 5.1% of their body weight. The researchers saw similar results when they implanted devices into the animals that gave them a steady dose of frovatriptan for 24 days.

“We found that these drugs, and one in particular, can lower body weight and improve glucose metabolism in less than a month, which is pretty impressive,” said Dr Liu.

Since triptans are generally prescribed for short-term use during migraines, Dr Liu suspects that patients would not have noticed the longer-term impacts on appetite and weight in the past.

To determine exactly how frovatriptan impacts food intake and weight, the researchers engineered mice to lack either Htr1b or Htr2c, the serotonin receptor targeted by fen-phen and lorcaserin. In mice without Htr1b, frovatriptan no longer could decrease appetite or cause weight loss, while cutting out Htr2c had no effect. This confirmed that the drug worked by targeting the serotonin 1B receptor.

“This finding could be important for drug development,” said Dr Liu. “We not only shed light on the potential to repurpose existing triptans but also brought attention to Htr1b as a candidate to treat obesity and regulate food intake.”

Source: UT Southwestern Medical Center

Categories : Mental HealthTags :

Histamine Involvement in Depression Revealed

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Histamine from inflammation dampens serotonin levels and antidepressants’ ability to boost them, according to experiments in mice models.

The findings, published in The Journal of Neuroscience add to mounting evidence that inflammation, and the accompanying release of the molecule histamine, affects serotonin, a key molecule responsible for mood in the brain.

Inflammation triggers the release of histamine in the body, increasing blood flow to affected areas to flood them with immune cells. While these effects help the body fight infections, both long-term and acute inflammation is increasingly linked to depression. There is already strong evidence that patients with both depression and severe inflammation are the ones most likely not to respond to antidepressants.

Dr Parastoo Hashemi, Lead Author, Imperial’s Department of Bioengineering, said: “Our work shines a spotlight on histamine as a potential key player in depression. This, and its interactions with the ‘feel-good molecule’ serotonin, may thus be a crucial new avenue in improving serotonin-based treatments for depression.”

Chemical messengers
Serotonin is a key target for depression-tackling drugs, and selective serotonin reuptake inhibitors (SSRIs) inhibit the re-absorption of serotonin in the brain, allowing it to circulate for longer and improve mood.

However, although SSRIs bring relief to many who take them, an increasing number of people are resistant to it. This could be due to the specific interactions between chemical messengers, or neurotransmitters, including serotonin and histamine.

With this in mind, researchers set out to investigate the relationship between histamine, serotonin, and SSRIs. They created tiny serotonin-measuring microelectrodes and put them into the hippocampus of the brains of live mice, an area known to regulate mood. The technique, known as fast scan cyclic voltammetry (FSCV), allowed them to measure brain serotonin levels in real time..

After placing the microelectrodes, they injected half the mice with lipopolysaccharide (LPS), an inflammation-causing toxin found in some bacteria, and half the mice with a saline solution as a control.

Within minutes of LPS injection, brain serotonin levels dropped, whereas they remained the same in control mice, demonstrating the rapid action of inflammatory responses on the brain and serotonin. Since LPS cannot cross the blood-brain barrier, it could not cause the drop in serotonin.
The inflammatory response triggered histamine in the brain which directly inhibited the release of serotonin by attaching to inhibitory receptors. 

To counter this, the researchers administered SSRIs to the mice, but they were much less able to boost serotonin levels than in control mice. They posited that this is because the SSRIs directly increased the amount of histamine in the brain, cancelling out its serotonin boosting action.

The researchers then administered histamine reducing drugs alongside the SSRIs to counter histamine’s inhibitory effects, and saw serotonin levels rise back to control levels. This appears to confirm the theory that histamine directly dampens serotonin release in the mouse brain. These histamine reducing drugs cause a whole-body reduction in histamine and are distinct from antihistamines taken for allergies, which block histamine’s effects on neurons.

A new molecule of interest
More work is needed before progressing to human studies. However, it is not currently feasible to use microelectrodes to make similar measurements in human brains, so the researchers are now looking at other ways to get a snapshot of the brain by looking at other organs which use serotonin and histamine, like the gut.

Source: Imperial College London