Serotonin IB

S100A10 was found to interact with the serotonin IB receptor increasing its presence at the cell membrane. S100A10 was found to be closely associated with the pathophysiology of depression. 

Other knockout models that could be used to validate candidate genes include mice that lack monoamine oxidase A (MAO-A), which have demonstrated altered behavior and alcohol tolerance [54]. Transgenic mice in which the dopamine transporter gene has been deleted show striking hyperactivity via enhanced persistence of dopamine which is not altered by cocaine or amphetamine administration [55]. Knockouts of the serotonin IB receptor are also available and are best used as models of vulnerability to drug abuse [56]. 

Dulawa SC, Hen R, Scearce-Levie K, Geyer M (1997) Serotonin IB receptor modulation of startle reactivity, habituation, and prepulse inhibition in wildtype and serotonin IB knock-out mice. Neiuoreport 132 125-134... 

Knock-out reduced depression-like behavior, increased serotonin IB receptors. Increased anxiety-related distress, increased... 

S100A11 Knock-out depression-like behavior, decreased response to sweet reward, reduced serotonin IB receptors. No obvious abnormalities... 

Young-Davies CL, Bennett-Clarke CA, Lane RD, Rhoades RW. Selective facilitation of the serotonin (IB) receptor causes disorganization of thalamic afferents and barrels in somatosensory cortex of rat. J Comp Neurol 2000 425 130-138. 

Hasegawa Y, et al. Association of a polymorphism of the serotonin IB receptor gene and alcohol dependence with inactive aldehyde dehydrogenase-2. J Neural Transm 2002 109(4) 513-521. 

SariY Serotonin( IB) receptors from protein to physiological function and behavior. Neurosci Biobehav Rev 2004 28 565-582. 

Rocha BA, Scearce-Levie K, Lucas JJ, et al. Increased vulnerability to cocaine in mice lacking the serotonin-IB receptor. Nature 1998 393(6681) 175-178. 

Enteric nerves control intestinal smooth muscle action and are connected to the brain by the autonomic nervous system. IBS is thought to result from dysregulation of this brain-gut axis. The enteric nervous system is composed of two gan-glionated plexuses that control gut innervation the submucous plexus (Meissner s plexus) and the myenteric plexus (Auerbach s plexus). The enteric nervous system and the central nervous system (CNS) are interconnected and interdependent. A number of neurochemicals mediate their function, including serotonin (5-hydroxytryptamine or 5-HT), acetylcholine, substance P, and nitric oxide, among others. 

Tricyclic antidepressants (TCAs) such as amitriptyline and doxepin have been used with some success in the treatment of IBS-related pain (Table 18-5). They modulate pain principally through their effect on neurotransmitter reuptake, especially norepinephrine and serotonin. Their helpfulness in functional gastrointestinal disorders seems independent of mood-altering effects normally associated with these agents. Low-dose TCAs (e.g., amitriptyline, desipramine, or doxepin 10 to 25 mg daily) may help patients with IBS who predominantly experience diarrhea or pain. 

Should analgesics prove insufficiently effective, ergotamine or one of the 5-HTi, agonists may help control the acute attack in most cases or prevent an imminent attack. The probable common mechanism of action is a stimulation of serotonin receptors of the 5-HTid (or perhaps also the IB and IF) subtype. Moreover, ergotamine has affinity for dopamine receptors ( nausea, eme-... 

Salichon N, Gaspar P, Upton AL, Picaud S, Hanoun N, Hamon M, De Maeyer EE, Mnrphy DL, Mossner R, Lesch KP, Hen R, Seif I (2001) Excessive activation of serotonin (5-HT) IB receptors disrupts the formation of sensory maps in monoamine oxidase A and 5-HT transporter knock-out mice. J Neurosci 21 884-896... 

HT interacts with a large diversity of G-protein-coupled receptors, namely the 5-HTi,2,4,5,6 and 7 families, and in addition with a ligand-gated cationic channel, 5-HT3. The diversity has been explained by the fact that serotonin is one of the oldest neurotransmitters in evolution. The 5-HTi receptor family (5-HTia,ib,id,ie andiF) couples mainly to Gi/o. 5-1 I I oa, 5-HT2B and 5-HT2C receptors couple to Gq/11. 5-HT4, 5-HT6, and 5-HT7 receptors couple to Gs. The 5-HT5A receptor couples principally to Gi/o. The 5-HTsb receptor seems to occur only in rodents, and no transduction mechanism has been identified. 

Domenech T, Beleta J, Palacios JM. Characterization of human serotonin ID and IB receptors using [3H]-GR-12,5743, a novel radiolabelled serotonin 5HT1D/1B receptor antagonist. Naunyn Schmiedebergs Arch Pharmacol 1997 356 328-334. 

Trillat AC, Malagie I, Scearce K, et al. Regulation of serotonin release in the frontal cortex and ventral hippocampus of homozygous mice lacking 5-HT IB receptors in vivo microdialysis studies. J Neurochem 1997 69 2019-2025. 

The enteric nervous system contains a significant percentage of the body s 5-hydroxytryptamine (serotonin, 5-HT). " Two types of serotonin exists within the gut serotonin type 3 (HT3) and serotonin type 4 (HT4), which are responsible for secretion, sensitization, and motility. FYevious studies show that there is an increase in the postprandial levels of 5-HT in those who suffer from diarrhea-predominant IBS when compared with nonsufferers. Therefore stimulation and antagonism of these serotonin receptors has become a focused area for research on new drug therapies for both diarrhea-and constipation-predominant disease. 

The newer serotonin receptor agonists and antagonists tegaserod and alosetron act on Gl-specific serotonin receptors to treat constipation-predominant and diarrhea-predominant IBS, respectively. However, both drugs are currently only indicated for women. Efficacy and safety in men has not been established because the initial manufacturer s sponsored clinical trials contained insufficient numbers of men with IBS to provide the necessary statistical power to prove efficacy and safety. Ongoing studies should determine if these drugs are indicated in men. 

Alosetron is a 5-HT3 receptor antagonist that inhibits serotonin receptors in the GI tract and is indicated in the treatment of irritable bowel syndrome (IBS) in women whose predominant bowel syndrome is diarrhea. The 5-HT3 recep-... 

In recent years, increased emphasis has been placed on the pharmacological treatment of visceral sensitivity in IBS patients. A possible role for serotonin in IBS has been suggested based on its known involvement in sensitization of nociceptor neurons in inflammatory conditions. This has led to the development of specific receptor modulators, such as tegaserod (see above). 

---