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Serotonin, Our Utility Hormone, Still Surprises


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New York Times


May 2, 2011


Job Description Grows for Our Utility Hormone




Just when you thought that serotonin was passé, and you’d tossed all your half-used bottles of S.S.R.I.-type antidepressants because the ones that didn’t give you nausea or smother your libido left you wondering whether you were in the placebo arm of a clinical trial, here comes a raft of new discoveries that sweeps the small, evolutionarily ancient and slyly powerful signaling molecule back on to center stage.


Researchers lately have learned that serotonin plays an impressive number of critical roles throughout the body, both below the neck and above it, and from the earliest days of prenatal pre-sentience. One team has found that serotonin starts seeping into the embryonic forebrain during the first trimester of pregnancy, helping to shape the basic neural circuitry that later in life will be applied to learning, emoting and consulting a psychiatrist.


More surprising still, Pat Levitt of the Zilkha Neurogenetic Institute at the University of Southern California and his colleagues reported in the April 21 issue of the journal Nature, the creator of all that architectonic prenatal serotonin turns out to be an organ long dismissed as a passive sieve: the placenta. Other researchers have determined that serotonin in the gut helps orchestrate the remodeling of bone, the lifelong buildup and breakdown of osteoclasts and osteoblasts that make the human skeleton such an exciting organ system to own.




“If I didn’t admit to being surprised by the scope of serotonin function, and how important it is to tissues like bone,” said Patricia Ducy, who studies the effect of serotonin on bone biology at Columbia University Medical Center, “I would be lying.”


Serotonin is a tiny molecule, a bibelot built of just 10 carbon atoms, a dozen hydrogens, two nitrogens and a single oxygen. The molecule was first detected in 1948, in blood serum, and it was shown be a vascular toning agent that causes blood vessels to constrict — hence its name, a conjoinment of “serum” and “tone.” Five years later, scientists found serotonin in brain extracts as well, and they soon learned that the recently invented hallucinogenic drug lysergic acid diethylamide worked by tapping into the brain’s serotonin system and that if you took too much LSD you might end up wearing hair garlands and overusing the word “wow.”




To synthesize their serotonin, humans and other species must start with tryptophan, an essential amino acid found in many dietary items, including turkey, cheese, tofu, nuts, seeds and bananas, a fruit that, despite its notorious comedic associations, always ends up on lists of “very wholesome foods with possible medicinal value.”


Much effort has been devoted to the study of how serotonin operates in the brain, where it serves as a neurotransmitter, a chemical that activates brain cells to fire messages at each other through their impulsive Morse code. In the adult brain, all serotonin is supplied by a handful of cells located in the hindbrain, atop the spinal cord, but those neurons share their bounty widely through filamentous projections.


Not surprisingly, the serotonin signaling system is wondrously complex. Scientists have identified at least 15 distinct serotonin receptors, proteins that clasp onto serotonin and react accordingly. In addition, there is the serotonin transporter, a janitorial protein that removes the serotonin from the little cleft between nerve cells once the molecule’s transmission task is through.


For all the intricacy, serotonin in the brain has a basic personality. “It’s a molecule involved in helping people cope with adversity, to not lose it, to keep going and try to sort everything out,” said Philip J. Cowen, a serotonin expert at Oxford University and the Medical Research Council. In the fine phrase of his Manchester University colleague Bill Deakin, “it’s the ‘Don’t panic yet’ neurotransmitter,” said Dr. Cowen. Given serotonin’s job description, disturbances in the system can contribute to depression, anxiety, panic attacks and mental calcification, an inability to see the world anew — at least in otherwise vulnerable people.


Dr. Cowen emphasizes that serotonin disruption alone does not directly cause depression. Experiments have shown that if you shut down serotonin production in normal people by subjecting them to an extreme tryptophan-free diet, they may not notice the difference; those with a history of depression, however, may well fall back into their gloom.


Prozac, Zoloft and other so-called serotonin-specific reuptake inhibitors seek to enhance serotonin trafficking by blocking the serotonin transporter, thus allowing the neurotransmitter to linger longer in neuronal vestibules and keep supplying its stimulus package to any shovel-ready receptor that will have it.


A newer class of antidepressants goes further, aiming not only at the transporter, but also at one or more of the 15 different serotonin receptors, an approach that may heighten the effectiveness of the drug while limiting the spillover side effects. Earlier this year, the Food and Drug Administration approved one of these pharmacological novelties, an antidepressant called Vilazodone, which is said to be reasonably free of some of the most vexing side effects seen in the standard transporter-only drugs, notably weight gain and sexual difficulties....


Much of the new serotonin research focuses on the molecule acting not as a neurotransmitter, a conveyor of information, but as a hormone, a shaper of tissues. In the new Nature paper, Dr. Levitt and his co-workers described their studies of early neural development in mice, and how they learned that, starting at around day 10 of gestation — the equivalent of roughly the eighth week in humans — the mouse forebrain was flooded with serotonin, and the bath continued to what would be the gestational midpoint. No other part of the brain was similarly exposed to serotonin — just the forebrain.


The researchers had previously gathered evidence that the serotonin served to stimulate the growth of new neural connections rather than incite synaptic activity in existing neurons; after all, the infrastructure of the forebrain was still too rudimentary to start making calls. But what was the source of the anabolic serotonin? Through an elegant series of experiments, the researchers ruled out other parts of the embryo, including the hindbrain.... The placenta synthesizes serotonin and ships it straight to the forebrain. “It makes sense that those circuits involved with mood, emotions, confronting challenges in the environment,” said Dr. Levitt, “were themselves shaped by the environment early on” — a placental tutorial.... “The only way the placenta can get tryptophan,” said Dr. Levitt, “is from the mother.”


Neuronal serotonin may be better known, but as it happens the vast bulk of the body’s serotonin supply, better than 95 percent, is synthesized outside the brain, mostly by the gut. The two serotonin stocks are kept strictly segregated by the blood-brain barrier, however, and are able to perform on entirely independent pathways.


New research suggests that our bones take advantage of both serotonin circuits, to manage the delicate dance between its two cellular castes: the constructive osteoblasts that build up the skeleton, patch the holes and repair cracks, and the destructive osteoclasts devoted to chipping rickety old bone tissue down.


As Dr. Ducy, Gerard Karsenty and their colleagues describe in a series of papers published in the Journal of Cell Biology, Nature Medicine and elsewhere, bone relies indirectly on serotonin cascades in the brain to stimulate the osteoblasts and inhibit the wrecking-crew osteoclasts.


Serotonin from the gut, on the other hand, keeps bone-making in check: it suppresses the osteoblasts from making fresh bone, but to the caustic osteoclasts is says neither yea nor nay. In experiments with severely osteoporotic mice and rats, the researchers showed that if they used a drug to cut the rodents’ production of gut serotonin by only 40 percent, they freed up the animals’ osteoblastic carpenters so well that the most hollowed-out skeletons were restored to a sturdy state of brand-new.


“We couldn’t find any side effects from the treatment,” Dr. Ducy said, “most likely because we didn’t have to totally wipe out serotonin synthesis to see the positive impact on bone.” Serotonin can be vital or spiteful, offering calm in adversity or skeletal porosity. Sometimes serotonin talks too much, and it’s best to just hang up the phone.

This is not medical advice. Discuss any decisions about your medical care with a knowledgeable medical practitioner.

"It has become appallingly obvious that our technology has surpassed our humanity." -- Albert Einstein

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Great find, Sur!


Wow (<< too much LSD...), serotonin is made during the first trimester of life!


The brain is a brain. The stomach is a brain. Now, the placenta is a brain!


The involvement of serotonin in bone-making makes me wonder about the role of SSRIs in the osteoporosis epidemic. (OK, at end of article, looks like a yes.)


Interesting about the etymology of the word!


Ack! New class of serotonin drug coming.


Fascinating info in this article.


Natalie's funny!

1996-97 - Paxil x 9 months, tapered, suffered 8 months withdrawal but didn't know it was withdrawal, so...

1998-2001 - Zoloft, tapered, again unwittingly went into withdrawal, so...

2002-03 - Paxil x 20 months, developed severe headaches, so...

Sep 03 - May 05 - Paxil taper took 20 months, severe physical, moderate psychological symptoms

Sep 03 - Jun 05 - took Prozac to help with Paxil taper - not recommended

Jul 05 to date - post-taper, severe psychological, moderate physical symptoms, improving very slowly

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