Posts tagged serotonin
Articles and news from the latest research reports.
Depression is detectable in the blood
Researchers at the MedUni Vienna have demonstrated the possibility of using a blood test to detect depression. While blood tests for mental illnesses have until recently been regarded as impossible, a recent study clearly indicates that, in principle, depression can in fact be diagnosed in this way and this could become reality in the not too distant future.
Serotonin transporter (SERT) is a protein in the cell membrane that facilitates the transport of the neurotransmitter serotonin (popularly known as the “happiness hormone”) into the cell. In the brain, serotonin transporter regulates neural depression networks. Depressive conditions can frequently be caused by a lack of serotonin. As a result, the serotonin transporter is also the point of action for the major antidepressant drugs.
The serotonin transporter, however, also occurs in large quantities in numerous other organs such as the intestines or blood. Recent studies have shown that the serotonin transporter in the blood works in exactly the same way as in the brain. In the blood, it ensures that blood platelets maintain the appropriate concentration of serotonin in the blood plasma.
Researchers at the MedUni Vienna have now used functional magnetic resonance imaging of the brain and pharmacological investigations to demonstrate that there is a close relationship between the speed of the serotonin uptake in blood platelets and the function of a depression network in the brain.
This network is termed the “default mode network” because it is primarily active at rest and processes content with strong self-reference. Findings from recent years have also demonstrated that it is actively suppressed during complex thought processes, which is essential for adequate levels of concentration. Interestingly, patients with depression find it difficult to suppress this network during thought processes, leading to negative thoughts and ruminations as well as poor concentration.
“This is the first study that has been able to predict the activity of a major depression network in the brain using a blood test. While blood tests for mental illnesses have until recently been regarded as impossible, this study clearly shows that a blood test is possible in principle for diagnosing depression and could become reality in the not too distant future,” explains study leader Lukas Pezawas from the Department of Biological Psychiatry at the University Department of Psychiatry and Psychotherapy within the MedUni Vienna. This result means that the diagnosis of depression through blood tests could become reality in the not too distant future.
Researchers Find Association Between SSRI Use During Pregnancy and Autism and Developmental Delays in Boys
In a study of nearly 1,000 mother-child pairs, researchers from the Bloomberg School of Public health found that prenatal exposure to selective serotonin reuptake inhibitors (SSRIs), a frequently prescribed treatment for depression, anxiety and other disorders, was associated with autism spectrum disorder (ASD) and developmental delays (DD) in boys. The study, published in the online edition of Pediatrics, analyzed data from large samples of ASD and DD cases, and population-based controls, where a uniform protocol was implemented to confirm ASD and DD diagnoses by trained clinicians using validated standardized instruments.
The study included 966 mother-child pairs from the Childhood Autism Risks from Genetics and the Environment (CHARGE) Study, a population-based case-control study based at the University of California at Davis’ MIND Institute. The researchers broke the data into three groups: Those diagnosed with autism spectrum disorder (ASD), those with developmental delays (DD) and those with typical development (TD). The children ranged in ages two to five. A majority of the children were boys – 82.5% in the ASD group were boys, 65.6% in the DD group were boys and 85.6% in the TD were boys. While the study included girls, the substantially stronger effect in boys alone suggests possible gender difference in the effect of prenatal SSRI exposure.
“We found prenatal SSRI exposure was nearly 3 times as likely in boys with ASD relative to typical development, with the greatest risk when exposure took place during the first trimester,” said Li-Ching Lee, Ph.D., Sc.M., psychiatric epidemiologist in the Bloomberg School’s Department of Epidemiology. “SSRI was also elevated among boys with DD, with the strongest exposure effect in the third trimester.”
The data analysis was completed by Rebecca Harrington, Ph.D., M.P.H, in conjunction with her doctoral dissertation at the Bloomberg School. Dr. Lee was one of her advisors.
Serotonin is critical to early brain development; exposure during pregnancy to anything that influences serotonin levels can have potential effect on birth and developmental outcomes. The prevalence of ADS continues to rise. According to the Centers for Disease Control and Prevention, an estimated 1 in 68 children in the U.S. is identified with ADS, and it is almost five times more common among boys than girls. One may question whether the increased use of SSRI in recent years is a contributor to the dramatic rise of ASD prevalence.
"This study provides further evidence that in some children, prenatal exposure to SSRIs may influence their risk for developing an autism spectrum disorder,” said Irva Hertz-Picciotto, Ph.D., M.P.H., chief of the Division of Environmental and Occupational Health in the UC Davis Department of Public Health Sciences and a researcher at the UC Davis MIND Institute. “This research also highlights the challenge for women and their physicians to balance the risks versus the benefits of taking these medications, given that a mother’s underlying mental-health conditions also may pose a risk, both to herself and her child.”
Regarding treatment, the authors note that maternal depression itself carries risks for the fetus, and the benefits of using SSRI during pregnancy should be considered carefully against the potential harm. The researchers also note that large sample studies are needed to investigate the effects in girls with ASD. Limitations of the study acknowledged include the difficulty in isolating SSRI effects from those of their indications for use, lack of information on SSRI dosage precluded dose-response analyses, and the relatively small sample of DD children resulted in imprecise estimates of association, which should be viewed with caution.
(Source: jhsph.edu)
Switching off anxiety with light
G protein coupled receptors play an important role in medicine and health
One receptor, which is important for the regulation of serotonin levels in the brain, is the 5-HT1A receptor. It belongs to a protein family called G protein coupled receptors (GPCRs). These receptors can activate different signalling pathways in cells to support or suppress various signalling events. “About 30 per cent of the current drugs target specifically GPCRs”, says Prof Dr Stefan Herlitze from the Department of General Zoology and Neurobiology at the RUB. Due to the lack of tools to control intracellular signalling pathways with high temporal and spatial accuracy, it was so far difficult to analyse these pathways precisely.
Coupling of visual pigments to serotonin receptors
Applying optogenetic methods the scientists in Bochum used cone opsins from the mouse and human eye to control specifically serotonin signalling pathways either with blue or red light. Prof Dr Stefan Herlitze has been working with optogenetic techniques since 2005 and is one of the pioneers in the field. The light-activated serotonin receptors can be switched on within milliseconds, are extremely light sensitive in comparison to other optogenetic tools and can be repetitively activated. “We hope that with the help of these optogenetic tools, we will be able to gain a better understanding about how anxiety and depression originate”, states RUB neuroscientist Dr Olivia Masseck.
Successful behavioural tests
The scientists also demonstrated that they were able to modulate mouse emotional behaviour using the light-activated receptors. When they switched on the serotonergic signals by light in a certain brain area, the mice became less anxious.
Brain Uses Serotonin To Perpetuate Chronic Pain Signals In Local Nerves
Setting the stage for possible advances in pain treatment, researchers at The Johns Hopkins University and the University of Maryland report they have pinpointed two molecules involved in perpetuating chronic pain in mice. The molecules, they say, also appear to have a role in the phenomenon that causes uninjured areas of the body to be more sensitive to pain when an area nearby has been hurt. A summary of the research will be published on Jan. 23 in the journal Neuron.
Image caption: Nerves in mouse skin that are actively responding to the painful stimulus capsaicin have been genetically engineered to glow green. Hairs appear in yellow. Credit: David Rini
"With the identification of these molecules, we have some additional targets that we can try to block to decrease chronic pain," says Xinzhong Dong, Ph.D., associate professor of neuroscience at the Johns Hopkins University School of Medicine and an early career scientist at Howard Hughes Medical Institute. "We found that persistent pain doesn’t always originate in the brain, as some had believed, which is important information for designing less addictive drugs to fight it."
Chronic pain that persists for weeks, months or years after an underlying injury or condition is resolved afflicts an estimated 20 to 25 percent of the population worldwide and about 116 million people in the U.S., costing Americans a total of $600 billion in medical interventions and lost productivity. It can be caused by everything from nerve injuries and osteoarthritis to cancer and stress.
In their new research, the scientists focused on a system of pain-sensing nerves within the faces of mice, known collectively as the trigeminal nerve. The trigeminal nerve is a large bundle of tens of thousands of nerve cells. Each cell is a long “wire” with a hub at its center; the hubs are grouped together into a larger hub. On one side of this hub, three smaller bundles of wires — V1, V2 and V3 — branch off. Each bundle contains individual pain-sensing wires that split off to cover a specific territory of the face. Signals are sent through the wires to the hubs of the cells and then travel to the spinal cord through a separate set of bundles. From the spinal cord, the signals are relayed to the brain, which interprets them as pain.
When the researchers pinched the V2 branch of the trigeminal nerve for a prolonged period of time, they found that the V2 and V3 territories were extra sensitive to additional pain. This spreading of pain to uninjured areas is typical of those experiencing chronic pain, but it can also be experienced during acute injuries, as when a thumb is hit with a hammer and the whole hand throbs with pain.
To figure out why, the researchers studied pain-sensing nerves in the skin of mouse ears. The smaller branches of the trigeminal V3 reach up into the skin of the lower ear. But an entirely different set of nerves is responsible for the skin of the upper ear. This distinction allowed the researchers to compare the responses of two unrelated groups of nerves that are in close proximity to each other.
To overcome the difficulty of monitoring nerve responses, Dong’s team inserted a gene into the DNA of mice so that the primary sensory nerve cells would glow green when activated. The pain-sensing nerves of the face are a subset of these.
When skin patches were then bathed in a dose of capsaicin — the active ingredient in hot peppers — the pain-sensing nerves lit up in both regions of the ear. But the V3 nerves in the lower ear were much brighter than those of the upper ear. The researchers concluded that pinching the connected-but-separate V2 branch of the trigeminal nerve had somehow sensitized the V3 nerves to “overreact” to the same amount of stimulus. (Watch nerves light up in this video.)
Applying capsaicin again to different areas, the researchers found that more nerve branches coming from a pinched V2 nerve lit up than those coming from an uninjured one. This suggests that nerves that don’t normally respond to pain can modify themselves during prolonged injury, adding to the pain signals being sent to the brain.
Knowing from previous studies that the protein TRPV1 is needed to activate pain-sensing nerve cells, the researchers next looked at its activity in the trigeminal nerve. They showed it was hyperactive in injured V2 nerve branches and in uninjured V3 branches, as well as in the branches that extended beyond the hub of the trigeminal nerve cell and into the spinal cord.
Next, University of Maryland experts in the neurological signaling molecule serotonin, aware that serotonin is involved in chronic pain, investigated its role in the TRPV1 activation study. The team, led by Feng Wei, M.D., Ph.D., blocked the production of serotonin, which is released from the brain stem into the spinal cord, and found that TRPV1 hyperactivity nearly disappeared.
Says Dong: “Chronic pain seems to cause serotonin to be released by the brain into the spinal cord. There, it acts on the trigeminal nerve at large, making TRPV1 hyperactive throughout its branches, even causing some non-pain-sensing nerve cells to start responding to pain. Hyperactive TRPV1 causes the nerves to fire more frequently, sending additional pain signals to the brain.”
Ketamine acts as antidepressant by boosting serotonin
Ketamine is a potent anesthetic employed in human and veterinary medicine, and sometimes used illegally as a recreational drug. The drug is also a promising candidate for the fast treatment of depression in patients who do not respond to other medications. New research from the RIKEN Center for Life Science Technologies in Japan demonstrates using PET imaging studies on macaque monkeys that ketamine increases the activity of serotoninergic neurons in the brain areas regulating motivation. The researchers conclude that ketamine’s action on serotonin, often called the “feel-good neurotransmitter”, may explain its antidepressant action in humans.
The study, published today in the journal Translational Psychiatry demonstrates that Positron Emission Tomography (PET) molecular imaging studies may be useful in the diagnosis of major depressive disorder in humans, as well as the development of new antidepressants.
Ketamine has recently been shown to have an antidepressant action with short onset and long-term duration in patients suffering from treatment-resistant major depressive disorder, who do not respond to standard medications such as serotonin reuptake inhibitors, monoamine oxidase inhibitors and tricyclic antidepressants. However, the mechanisms underlying ketamine’s action on the depressive brain have remained unclear.
To understand the effects of ketamine on the serotonergic system in the brain, Dr. Hajime Yamanaka and Dr. Hirotaka Onoe, who has pioneered PET imaging on conscious non-human primates, together with an international team, performed a PET study on rhesus monkeys.
The team performed PET imaging studies on four rhesus monkeys with two tracer molecules related to serotonin (5-HT) that bind highly selectively to the serotonin 1B receptor 5-HT1B and the serotonin transporter SERT.
From the analysis of the 3 dimensional images generated by the PET scans, the researchers could infer that ketamine induces an increase in the binding of serotonin to its receptor 5-HT1B in the nucleus accumbens and the ventral pallidum, but a decrease in binding to its transporter SERT in these brain regions. The nucleus accumbens and the ventral pallidum are brain regions associated with motivation and both have been shown to be involved in depression.
In addition, the researchers demonstrate that treatment with NBQX, a drug known to block the anti-depressive effect of ketamine in rodents by selectively blocking the glutamate AMPA receptor, cancels the action of ketamine on 5-HT1B but not on SERT binding.
Taken together, these findings indicate that ketamine may act as an antidepressant by increasing the expression of postsynaptic 5-HT1B receptors, and that this process is mediated by the glutamate AMPA receptor.
A Personal Antidepressant for Every Genome
TAU researchers discover gene that may predict human responses to specific antidepressants
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants, but they don’t work for everyone. What’s more, patients must often try several different SSRI medications, each with a different set of side effects, before finding one that is effective. It takes three to four weeks to see if a particular antidepressant drug works. Meanwhile, patients and their families continue to suffer.
Now researchers at Tel Aviv University have discovered a gene that may reveal whether people are likely to respond well to SSRI antidepressants, both generally and in specific formulations. The new biomarker, once it is validated in clinical trials, could be used to create a genetic test, allowing doctors to provide personalized treatment for depression.
Doctoral students Keren Oved and Ayelet Morag led the research under the guidance of Dr. David Gurwitz of the Department of Molecular Genetics and Biochemistry at TAU’s Sackler Faculty of Medicine and Dr. Noam Shomron of the Department of Cell and Developmental Biology at TAU’s Sackler Faculty of Medicine and Sagol School of Neuroscience. Sackler faculty members Prof. Moshe Rehavi of the Department of Physiology and Pharmacology and Dr. Metsada Pasmnik-Chor of the Bioinformatics Unit were coauthors of the study, published in Translational Psychiatry.
"SSRIs only work for about 60 percent of people with depression," said Dr. Gurwitz. "A drug from other families of antidepressants could be effective for some of the others. We are working to move the treatment of depression from a trial-and-error approach to a best-fit, personalized regimen."
Good news for the depressed
More than 20 million Americans each year suffer from disabling depression that requires clinical intervention. SSRIs such as Prozac, Zoloft, and Celexa are the newest and the most popular medications for treatment. They are thought to work by blocking the reabsorption of the neurotransmitter serotonin in the brain, leaving more of it available to help brain cells send and receive chemical signals, thereby boosting mood. It is not currently known why some people respond to SSRIs better than others.
To find genes that may be behind the brain’s responsiveness to SSRIs, the TAU researchers first applied the SSRI Paroxetine — brand name Paxil — to 80 sets of cells, or “cell lines,” from the National Laboratory for the Genetics of Israeli Populations, a biobank of genetic information about Israeli citizens located at TAU’s Sackler Faculty of Medicine and directed by Dr. Gurwitz. The TAU researchers then analyzed and compared the RNA profiles of the most and least responsive cell lines. A gene called CHL1 was produced at lower levels in the most responsive cell lines and at higher levels in the least responsive cell lines. Using a simple genetic test, doctors could one day use CHL1 as a biomarker to determine whether or not to prescribe SSRIs.
"We want to end up with a blood test that will allow us to tell a patient which drug is best for him," said Oved. "We are at the early stages, working on the cellular level. Next comes testing on animals and people."
Rethinking how antidepressants work
The TAU researchers also wanted to understand why CHL1 levels might predict responsiveness to SSRIs. To this end, they applied Paroxetine to human cell lines for three weeks — the time it takes for a clinical response to SSRIs. They found that Paroxetine caused increased production of the gene ITGB3 — whose protein product is thought to interact with CHL1 to promote the development of new neurons and synapses. The result is the repair of dysfunctional signaling in brain regions controlling mood, which may explain the action of SSRI antidepressants.
This explanation differs from the conventional theory that SSRIs directly relieve depression by inhibiting the reabsorption of the neurotransmitter serotonin in the brain. Dr. Shomron adds that the new explanation resolves the longstanding mystery as to why it takes at least three weeks for SSRIs to ease the symptoms of depression when they begin inhibiting reabsorption after a couple days — the development of neurons and synapses takes weeks, not days.
The TAU researchers are working to confirm their findings on the molecular level and with animal models. Adva Hadar, a master’s student in Dr. Gurwitz’s lab, is using the same approach to find biomarkers for the personalized treatment of Alzheimer’s disease.
(Source: aftau.org)
Who learns from the carrot, and who from the stick?
To flexibly deal with our ever-changing world, we need to learn from both the negative and positive consequences of our behaviour. In other words, from punishment and reward. Hanneke den Ouden from the Donders Institute in Nijmegen demonstrated that serotonin and dopamine related genes influence how we base our choices on past punishments or rewards. This influence depends on which gene variant you inherited from your parents. These results were published in Neuron on 20 November.
The brain chemicals dopamine and serotonin partly determine our sensitivity to reward and punishment. At least, this was a common assumption. Hanneke den Ouden and Roshan Cools investigated this assumption together with colleagues from the Donders Institute and New York University. Den Ouden explains: ‘We used a simple computer game to test the genetic influence of the genes DAT1 and SERT, as these genes influence dopamine and serotonin. We discovered that the dopamine gene affects how we learn from the long-term consequences of our choices, while the serotonin gene affects our choices in the short term.’
Online game
‘In nearly 700 people we analysed which variant of the SERT and the DAT1 genes they had’, Den Ouden describes. ‘Using an online game, we investigated how well people are able to adjust their choice strategy after receiving a reward or a punishment.’ The players would repeatedly choose one of two symbols. Symbol A usually resulted in a reward whereas symbol B usually resulted in punishment. Halfway through the game, these rules were reversed. The game allowed the researchers to measure how flexible people are in adjusting their choices when the rules change. But it also showed whether people impulsively change their choice when the computer happened to give misleading feedback.
Different genes, different strategies
Den Ouden: ‘Different players use different strategies, which depend on their genetic material. People’s tendency to change their choice immediately after receiving a punishment depends on which serotonin gene variant they inherited from their parents. The dopamine gene variant, on the other hand, exerts influence on whether people can stop themselves making the choice that was previously rewarded, but no longer is.’
This study shows that dopamine and serotonin are important for different forms of flexibility associated with receiving reward and punishment. Many neuropsychiatric disorders caused by abnormal dopamine and/or serotonin levels are associated with forms of inflexibility, for example addiction, anxiety, or Parkinson’s disease. So this study not only tells us more about the heritability of our choice behaviour; a better understanding of the relationship between brain chemicals and behaviour in healthy people will ultimately help to provide us with better insight into these neuropsychiatric disorders.
(Source: ru.nl)
Individuals Genetically Predisposed to Anxiousness May Be Less Likely to Volunteer and Help Others
Scientists increasingly are uncovering answers for human behavior through genetic research. Now, a University of Missouri researcher has found that prosocial behavior, such as volunteering and helping others, is related to the same gene that predisposes individuals to anxiety disorders. Helping such individuals cope with their anxiety may increase their prosocial behavior, the researcher said.
“Prosocial behavior is linked closely to strong social skills and is considered a marker of individuals’ health and well-being,” said Gustavo Carlo, Millsap Professor of Diversity in MU’s College of Human Environmental Sciences. “Social people are more likely to be healthier, excel academically, experience career success and develop deeper interpersonal relationships that may help alleviate stress.”
Carlo and his colleagues found that, on average, those individuals who carried the genotype associated with higher social anxiety were less likely to engage in prosocial behavior.
“Previous research has shown that the brain’s serotonin neurotransmitter system plays an important role in regulating emotions,” said study co-author Scott Stoltenberg, an associate professor at the University of Nebraska-Lincoln. “Our findings suggest that individual differences in social anxiety levels are influenced by this serotonin system gene and that these differences help to partially explain why some people are more likely than others to behave prosocially. Studies like this one show that biological factors are critical influences on how people interact with one another.”
Because prosocial behavior is linked to genetically based anxiety, Carlo suggests that helping nervous individuals cope with their social anxiety through targeted efforts, such as encouragement, support, counseling and medication, could help them engage in more prosocial behavior.
“Some forms of anxieties can be very debilitating for individuals,” Carlo said. “When people have severe levels of social anxiety, such as agoraphobia, which is the fear of public places and large crowds, they will avoid social situations altogether and miss the prosocial opportunities.”
Carlo said that it is difficult to distinguish how much of prosocial behavior is based on learned environmental behavior and how much is biologically based.
“The nature-versus-nurture debate is always interesting,” Carlo said. “However, I think that in our contemporary models of human behavior, we are beginning to understand the interplay between biology and the environment.”
Much of Carlo’s previous study on prosocial development has focused on how environmental influences, such as family relationships, influence prosocial behavior. This study brings researchers closer to understanding the effect that individuals’ biological makeup has on their behaviors, Carlo said.
Birth gets the brain ready to sense the world
Neurons that process sensory information such as touch and vision are arranged in precise, well-characterized maps that are crucial for translating perception into understanding. A study published by Cell Press on October 14 in the journal Developmental Cell reveals that the actual act of birth in mice causes a reduction in a brain chemical called serotonin in the newborn mice, triggering sensory maps to form. The findings shed light on the key role of a dramatic environmental event in the development of neural circuits and reveal that birth itself is one of the triggers that prepares the newborn for survival outside the womb.
"Our results clearly demonstrate that birth has active roles in brain formation and maturation," says senior study author Hiroshi Kawasaki of Kanazawa University in Japan. "We found that birth regulates neuronal circuit formation not only in the somatosensory system but also in the visual system. Therefore, it seems reasonable to speculate that birth actually plays a wider role in various brain regions."
Mammals ranging from mice to humans have brain maps that represent various types of sensory information. In a region of the rodent brain known as the barrel cortex, neurons that process tactile information from whiskers are arranged in a map corresponding to the spatial pattern of whiskers on the snout, with neighboring columns of neurons responding to stimulation of adjacent whiskers. Although previous studies have shown that the neurotransmitter serotonin influences the development of sensory maps, its specific role during normal development has not been clear until now.
In this new study, Kawasaki and his team find that the birth of mouse pups leads to a drop in serotonin levels in the newborn’s brain, triggering the formation of neural circuits in the barrel cortex and in the lateral geniculate nucleus (LGN), a brain region that processes visual information. When mice were treated with drugs that either induced preterm birth or decreased serotonin signaling, neural circuits in the barrel cortex as well as in the LGN formed more quickly. Conversely, neural circuits in the barrel cortex failed to form when the mice were treated with a drug that increased serotonin signaling, suggesting that a reduction in levels of this neurotransmitter is crucial for sensory map formation.
Because serotonin also plays a key role in mental disorders, it is possible that abnormalities in birth processes and the effects on subsequent serotonin signaling and brain development could increase the risk of psychiatric diseases. “Uncovering the entire picture of the downstream signaling pathways of birth may lead to the development of new therapeutic methods to control the risk of psychiatric diseases induced by abnormal birth,” Kawasaki says.
(Source: eurekalert.org)
Researchers Pinpoint Molecular Path that Makes Antidepressants Act Quicker in Mouse Model
Understanding alternate pathways for how mental meds work could lead to faster-acting drug targets
The reasons behind why it often takes people several weeks to feel the effect of newly prescribed antidepressants remains somewhat of a mystery – and likely, a frustration to both patients and physicians.
(Image: Mouse hippocampus expressing the Cre- virus. Credit: Julie Blendy, PhD; Brigitta Gunderson, PhD; Perelman School of Medicine, University of Pennsylvania)
Julie Blendy, PhD, professor of Pharmacology, at the Perelman School of Medicine, University of Pennsylvania; Brigitta Gunderson, PhD, a former postdoctoral fellow in the Blendy lab, and colleagues, have been working to find out why and if there is anything that can be done to shorten the time in which antidepressants kick in.
“Our goal is to find ways for antidepressants to work faster,” says Blendy.
The proteins CREB and CREM are both transcription factors, which bind to specific DNA sequences to control the “reading” of genetic information from DNA to messenger RNA (mRNA). Both CREB and CREM bind to the same 8-base-pair DNA sequence in the cell nucleus. But, the comparative influence of CREM versus CREB on the action of antidepressants is a “big unknown,” says Blendy.
CREB, and CREM to some degree, has been implicated in the pathophysiology of depression, as well as in the efficacy of antidepressants. However, whenever CREB is deleted, CREM is upregulated, further complicating the story.
Therefore, how an antidepressant works on the biochemistry and behavior in a mouse in which the CREB protein is deleted only in the hippocampus versus a wild type mouse in which CREM is overexpressed let the researchers tease out the relative influence of CREB and CREM on the pharmacology of an antidepressant. They saw the same results in each type of mouse line – increased nerve-cell generation in the hippocampus and a quicker response to the antidepressant. Their findings appear in the Journal of Neuroscience.
“This is the first demonstration of CREM within the brain playing a role in behavior, and specifically in behavioral outcomes, following antidepressant treatment,” says Blendy.
A Flood of Neurotransmitters
Antidepressants like SSRIs, NRIs, and older tricyclic drugs work by causing an immediate flood of neurotransmitters like serotonin, norepinephrine, and in some cases dopamine, into the synaptic space. However, it can take three to four weeks for patients to feel changes in mental state. Long-term behavioral effects of the drugs may take longer to manifest themselves, because of the need to activate CREB downstream targets such as BDNF and trkB, or as of yet unidentified targets, which could also be developed as new antidepressant drug targets.
The Penn team compared the behavior of the control, wild-type mice to the CREB mutant mice using a test in which the mouse is trained to eat a treat – Reese’s Pieces, to be exact – in the comfort of their home cage. The treat-loving mice are then placed in a new cage to make them anxious. They are given the treat again, and the time it takes for the mouse to approach the treat is recorded.
Animals that receive no drug treatment take a long time to venture out into the anxious environment to retrieve the treat, however, if given an antidepressant drug for at least three weeks, the time it takes a mouse to get the treat decreases significantly, from about 400 seconds to 100 seconds. In mice in which CREB is deleted or in mice in which CREM is upregulated, this reduction happens in one to two days versus the three weeks seen in wild-type mice.
The accelerated time to approach the treat in mice on the medication was accompanied by an increase in new nerve growth in the hippocampus.
“Our results suggest that activation of CREM may provide a means to accelerate the therapeutic efficacy of current antidepressant treatment,” says Blendy. Upregulation of CREM observed after CREB deletion, appears to functionally compensate for CREB loss at a behavioral level and leads to maintained or increased expression of some CREB target genes. The researchers’ next step is to identify any unique CREM target genes in brain areas such as the hippocampus, which may lead to the development of faster-acting antidepressants.
(Source: uphs.upenn.edu)