Serotonin for ADHD

Serotonin May Be Better Target For ADHD Treatment Researchers at the Howard Hughes Medical Institute (HHMI) at Duke University have discovered that Ritalin and other stimulants exert their paradoxical calming effects by boosting serotonin levels in the brain. Elevating serotonin appears to restore the delicate balance between the brain chemicals dopamine and serotonin and calms hyperactivity, says HHMI investigator Marc Caron at Duke University Medical Center. Caron is an author of the study published in the January 15 issue of the journal Science. Attention deficit hyperactivity disorder (ADHD) affects three to six per cent of school-aged children. Symptoms include restlessness, impulsiveness, and difficulty concentrating. Stimulants commonly used to treat ADHD are so effective that "researchers haven't really taken the time to investigate how they work," says Caron. Previous dogma, says Caron, held that the calming action of Ritalin works through the neurotransmitter dopamine. Specifically, researchers believed that Ritalin and other stimulants interact with the dopamine transporter protein (DAT), a housekeeper of sorts for nerve pathways. After a nerve impulse moves from one neuron to another, DAT removes residual dopamine from the synaptic cleft-the space between two neurons-and repackages it for future use. Caron's team suspected that dopamine wasn't the only key to understanding ADHD, so they turned to mice in which they had "knocked out" the gene that codes for DAT. Since there is no DAT to "mop up" dopamine from the synaptic cleft, the brains of the mice are flooded with dopamine. The excess dopamine causes restlessness and hyperactivity, behaviors that are strikingly similar to those exhibited by children with ADHD. When placed in a maze that normal mice negotiate in less than three minutes, the knockout mice became distracted-performing extraneous activities such as sniffing and rearing - and they failed to finish in less than five minutes. The knockout mice also seemed unable to suppress inappropriate impulses - another hallmark of ADHD. Surprisingly, the knockout mice were still calmed by Ritalin, Dexedrine and other stimulants even though they lacked the protein target on which Ritalin and Dexedrine were thought to act. "That caused us to look for other systems that these stimulants might affect," says Caron. To test whether the stimulants interact with dopamine through another mechanism, the researchers administered Ritalin to the normal and knockout mice and monitored their brain levels of dopamine. Ritalin boosted dopamine levels in the normal mice, but it did not alter dopamine levels in knockout mice. That result implied that "Ritalin could not be acting on dopamine," says Caron. They then studied whether the stimulants altered levels of the neurotransmitter serotonin. The scientists administered Prozac - a well-known inhibitor of serotonin reuptake - to the knockout mice. After ingesting Prozac, the knockout mice showed dramatic declines in hyperactivity. "This suggests that rather than acting directly on dopamine, the stimulants create a calming effect by increase serotonin levels," Caron says. "Our experiments imply that proper balance between dopamine and serotonin are key," says Raul Gainetdinov, a member of Caron's research team. "Hyperactivity may develop when the relationship between dopamine and serotonin is thrown off balance." The brain has 15 types of receptors that bind to serotonin, and Gainetdinov is now trying to determine which specific serotonin receptors mediate the effects of Ritalin. The hope, says Caron, "is that we can replace Ritalin with a very specific compound that targets a single subset of receptors." While Prozac calmed hyperactivity in the knockout mice, Gainetdinov says that "Prozac isn't the best, because it isn't very selective." Caron and Gainetdinov are optimistic that a new generation of compounds that interact more specifically with the serotonin system will prove to be safer and more effective for treatments for ADHD.

Serotonin's effects on multiple body systems

One Dangerous Deficiency Links IBS, Migraines, and More Health News By VRP Staff When you think of serotonin deficiency, the first consequence that might spring to mind is depression. And if so, you’d be right. But there’s more to this neurotransmitter than meets the eye—a lot more. Migraines, irritable bowel syndrome, fibromyalgia, obesity, even asthma… believe it or not, all of these serious conditions can be traced back to depleted serotonin levels. And the effects on your body can be as damaging as they are diverse. Serotonin is one of your brain’s most crucial messengers. It’s released by your neurons to send signals to other neurons, after which it’s returned to its original parent neuron to be reused. But if your levels are low, serotonin’s time on your synapse is cut short. It’s recaptured before it can finish its job—at a very high cost to your health, mentally and physically. In addition to depression, low levels of serotonin–and its precursor tryptophan–have been linked to binge eating, carbohydrate cravings, and weight gain.1 Studies show that obese and overweight diabetic patients have levels that are well below normal–and in clinical trials, increased brain serotonin led to both reduced caloric intake and resulting weight loss.2–4 But it’s not just your waistline that benefits from this critical neurotransmitter. Studies have shown that increasing serotonin levels can fight insomnia by improving sleep continuity.5 Research also shows that increased serotonin relieves migraines as effectively as standard drug therapy and aids in relief of chronic tension headaches.6–7 This same ability has made it a unique target in the treatment of fibromyalgia, with serotonin deficiency implicated for lower pain thresholds and higher clinical measures of perceived pain in patients.8–10 In an even more surprising connection, serotonin has also been identified as a major player in gut motility.11–12 Special serotonin–releasing cells can be found throughout your digestive system, responsible for stimulating peristaltic motion and pushing waste through your digestive tract.13 Even the development and severity of asthma has been linked to depression, anxiety, and low–serotonin related disorders—revealing yet another function under this neurotransmitter’s powerful influence.14 Proper levels of serotonin are essential for your health—and one way to ensure higher levels of this neurotransmitter is by boosting your intake of tryptophan, an essential amino acid found in high–protein foods that is responsible for serotonin synthesis in your brain. Research has shown that supplementing with tryptophan (and its metabolite 5–hydroxytryptophan, or 5–HTP) can replenish serotonin naturally and effectively—easing depression, anxiety, migraines, insomnia, and fibromyalgia symptoms in several clinical studies.15–17 References: 1. Gendall KA, Joyce PR. Meal–induced changes in tryptophan:LNAA ratio: effects on craving and binge eating. Eat Behav. 2000 Sep;1(1):53–62. 2. Breum L, Rasmussen MH, Hilsted J, Fernstrom JD. Twenty–four–hour plasma tryptophan concentrations and ratios are below normal in obese subjects and are not normalized by substantial weight reduction. Am J Clin Nutr. 2003 May;77(5):1112–1118. 3. Ceci F, Cangiano C, Cairella M, et al. The effects of oral 5–hydroxytryptophan administration on feeding behavior in obese adult female subjects. J Neural Transm 1989;76(2):109–117. 4. Cangiano C, Ceci F, Cascino A, et al. Eating behavior and adherence to dietary prescriptions in obese adult subjects treated with 5–hydroxytryptophan. Am J Clin Nutr 1992 Nov;56(5):863–867. 5. Riemann D, Vorderholzer U. Treatment of depression and sleep disorders. Significance of serotonin and L–tryptophan in pathophysiology and therapy. Fortschr Med. 1998 Nov;116(32):40–42. 6. Titus F, Dávalos A, Alom J, Codina A. 5–Hydroxytryptophan versus methysergide in the prophylaxis of migraine. Randomized clinical trial. Eur Neurol. 1986;25(5):327–329. 7. Ribeiro CA. L–5–Hydroxytryptophan in the prophylaxis of chronic tension–type headache: a double–blind, randomized, placebo–controlled study. For the Portuguese Head Society. Headache. 2000 Jun;40(6):451–456. 8. Birdsall TC. 5–Hydroxytryptophan: a clinically–effective serotonin precursor. Altern Med Rev. 1998 Aug;3(4):271–280. 9. Hrycaj P, Stratz T, Muller W. Platelet 3Himipramine uptake receptor density and serum serotonin levels in patients with fibromyalgia/fibrositis syndrome. J Rheumatol. 1993;20:1986–1988. [letter] 10. Russell IJ, Michalek JE, Vipraio GA, et al. Platelet 3H–imipramine uptake receptor density and serum serotonin levels in patients with fibromyalgia/fibrositis syndrome. J Rheumatol 1992;19:104–109. 11. Fayyaz M, Lackner JM. Serotonin receptor modulators in the treatment of irritable bowel syndrome. Ther Clin Risk Manag. 2008 Feb;4(1):41–48. 12. Gershon MD. The enteric nervous system: a second brain. Hosp Pract (Minneap). 1999 Jul 15;34(7):31–32,35–38,41–42. 13. Grider JR. Desensitization of the peristaltic reflex induced by mucosal stimulation with the selective 5–HT4 agonist tegaserod. Am J Physiol Gastrointest Liver Physiol. 2006 Feb;290(2):G319–G327. 14. Goodwin RD, Sourander A, Duarte CS, et al. Do mental health problems in childhood predict chronic physical conditions among males in early adulthood? Evidence from a community–based prospective study. Psychol Med. 2008 May 28:1–11. 15. Poldinger W, Calanchini B, Schwarz W. A functional approach to depression: serotonin deficiency as a target syndrome in a comparison of 5–hydroxytryptophan and fluvoxamine. Psychopathology. 1991;24:53–81. 16. Kahn RS, Westenberg HG. L–5–hydroxytryptophan in the treatment of anxiety disorders. J Affect Disord. 1985 Mar–Apr;8(2):197–200. 17. Puttini PS, Caruso I. Primary fibromyalgia and 5–hydroxy–L–tryptophan: a 90 day open study. J Int Med Res. 1992;20:182–189.