The expanded biology of serotonin

Abstract

Serotonin is perhaps best known as a neurotransmitter that modulates neural activity and a wide range of neuropsychological processes, and drugs that target serotonin receptors are used widely in psychiatry and neurology. However, most serotonin is found outside the central nervous system, and virtually all of the 15 serotonin receptors are expressed outside as well as within the brain. Serotonin regulates numerous biological processes including cardiovascular function, bowel motility, ejaculatory latency, and bladder control. Additionally, new work suggests that serotonin may regulate some processes, including platelet aggregation, by receptor-independent, transglutaminase-dependent covalent linkage to cellular proteins. We review this new "expanded serotonin biology" and discuss how drugs targeting specific serotonin receptors are beginning to help treat a wide range of diseases.

Figure 1

Central serotonergic pathways, effects, and drugs. In the central nervous system (CNS), serotonin is almost exclusively produced in neurons originating in the raphe nuclei located in the midline of the brainstem. These serotonin-producing neurons form the largest and most complex efferent system in the human brain. The most caudal raphe innervate the spinal cord, while the more rostral raphe, the dorsal raphe nucleus and the medial raphe nucleus, innervate much of the rest of the CNS by diffuse projections. Indeed, virtually every cell in the brain is close to a serotonergic fiber, and nearly all behaviors as well as many other brain functions are regulated by serotonin. Not surprisingly, serotonin receptors and transporters are a major focus of CNS drug development, and many current medications modulate serotonin neurotransmission. 5-HT, serotonin; MAOI, monoamine oxidase inhibitor; SSRI, selective serotonin reuptake inhibitor.

Figure 2

Myriad effects of serotonin outside the central nervous system. 5-HT, serotonin; AV, atrioventricular; CHF, congestive heart failure; HPA, hypothalamic-pituitary-adrenal; HTN, hypertension; IBS, irritable bowel syndrome; SIDS, sudden infant death syndrome.