Serotonin

Serotonin Synthesis, Release, and Inactivation

• The neurotransmitter 5-HT is synthesized from the amino acid tryptophan in two biochemical reactions. The first and rate-limiting reaction is catalyzed by the enzyme TPH.
• Brain 5-HT synthesis is controlled, in part, by tryptophan availability. Tryptophan entry into the brain from the bloodstream is determined by the plasma ratio of tryptophan to other large neutral amino acids (LNAA) that compete for transport across the blood–brain barrier.
• 5-HT synthesis is increased by several methods including direct tryptophan administration (tryptophan loading), consumption of proteins with very high tryptophan content, or consumption of a high-carbohydrate, low-protein meal. 5-HT synthesis is reduced by administration of an amino acid mixture lacking tryptophan, which causes acute tryptophan depletion.
• In healthy subjects, modest increases in the tryptophan-to-LNAA ratio produced by tryptophan loading usually have no effect on mood or cognition, whereas larger increases can positively enhance mood and cognition, and extremely high increases can exert negative effects on these processes. Acute tryptophan depletion generally does not affect mood in healthy participants but can cause symptom relapse in remitted depressed patients who are under treatment with serotonergic antidepressant drugs. Tryptophan depletion in healthy people can impair memory consolidation of verbal information.
• VMAT2 is responsible for loading 5-HT into synaptic vesicles for subsequent release.
• Serotonin release is inhibited by autoreceptors located on the cell body, dendrites, and terminals of serotonergic neurons. The terminal autoreceptors are of either the 5-HT_1B or 5-HT_1D subtype, depending on the species, whereas the somatodendritic autoreceptors are of the 5-HT_1A subtype.
• Several compounds have been identified that cause 5-HT release, one of which is MDMA. At high doses, this drug can produce serotonergic toxicity characterized by long-lasting depletion of 5-HT and other markers of serotonergic neurons.
• Serotonergic transmission is terminated by reuptake of 5-HT from the extracellular fluid. This process is mediated by the 5-HT transporter, which is an important target of several antidepressant drugs.
• Serotonin is ultimately metabolized by MAO-A to form the major breakdown product 5-HIAA.

Organization and Function of the Serotonergic System

• Most of the serotonergic neurons in the CNS are associated with the raphe nuclei of the brainstem. Together, the cells of the dorsal and median raphe nuclei send 5-HT–containing fibers to virtually all forebrain areas.
• Dorsal raphe neuronal firing varies with behavioral state and in response to rewards and punishments. Tonic firing is slow and regular in the awake state, becomes even slower in slow-wave sleep, and completely ceases during REM sleep. Phasic bursts of activity occur in response to rewarding and punishing stimuli. These phasic bursts are controlled by many different synaptic inputs, including excitatory inputs using the neurotransmitters glutamate and acetylcholine and inhibitory inputs using the neurotransmitter GABA.
• At least 14 different 5-HT receptor subtypes have been identified. Some of these fall within groups, such as the 5-HT1 family (5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT_1E, and 5-HT_1F) and a smaller group of three 5-HT₂ receptors (5-HT_2A, 5-HT_2B, and 5-HT_2C). The remaining 5-HT receptors are designated 5-HT₃, 5-HT₄, 5-HT_5A, 5-HT_5B, 5-HT₆, and 5-HT₇. All of the 5-HT receptors are metabotropic, except for the 5-HT₃ receptor, which is an excitatory ionotropic receptor.
• Two of the best-characterized 5-HT receptor subtypes are the 5-HT_1A and 5-HT_2A receptors. High levels of 5-HT_1A receptors have been found in the hippocampus, the septum, parts of the amygdala, and the dorsal raphe nucleus. In the raphe nuclei, including the dorsal raphe, these receptors are mainly somatodendritic autoreceptors on the serotonergic neurons themselves. In other brain areas, 5-HT_1A receptors are found on postsynaptic neurons that receive serotonergic input. 5-HT_1A receptors function by inhibiting cAMP formation and by enhancing the opening of K⁺ channels within the cell membrane. Among a variety of compounds that act on the 5-HT_1A receptor subtype are the agonist 8-OH-DPAT and the antagonist WAY 100635.
• There are 5-HT_2A receptors in the neocortex, striatum, and nucleus accumbens, as well as in other brain regions. This receptor subtype activates the phosphoinositide second-messenger system, which increases the amount of free Ca²⁺ within the cell and stimulates protein kinase C. When given to rodents, 5-HT_2A receptor agonists such as DOI trigger a head-twitch response. In humans, such drugs (which include LSD) produce hallucinations. Certain drugs used in the treatment of schizophrenia can block 5-HT_2A receptors, and some researchers hypothesize that such blockade may reduce certain harmful side effects usually associated with antischizophrenic medications.
• Other 5-HT receptor subtypes are currently targeted for specific medical conditions. Thus, 5-HT_1B/1D agonists such as sumatriptan and zolmitriptan are used for the treatment of migraine headaches, whereas 5-HT₃ antagonists such as ondansetron, granisetron, and palonosetron offer relief from the nausea and vomiting that can be produced by cancer chemotherapy and radiation treatments.
• Mutant mice in which the Tph2 gene has been knocked out lack the capacity to synthesize 5-HT in the nervous system. Such mice suffer postnatal growth retardation and increased mortality. They exhibit heightened aggressiveness, impulsive and compulsive behaviors, and impaired social communication, but less anxiety (at least under some conditions) than wild-type mice. Physiologically,Tph2-knockout mice suffer from poor thermoregulation and abnormal respiration, manifested in part by episodes of apnea during early postnatal development. Serotonergic neurons are believed to be important in the brain’s response to hypercapnia, which has led to the hypothesis that abnormalities in the serotonergic system may be involved in SIDS and SUDEP.
• Pharmacological approaches have elucidated a key role for various 5-HT receptors in the regulation of many functions, including eating behavior (5-HT_1B, 5-HT_2C, and 5-HT₆), anxiety (5-HT_1A, 5-HT_2A, 5-HT_2C, and 5-HT₆), neuropathic pain (5-HT_1A, 5-HT_1B, 5-HT_2C, and 5-HT₇), learning and memory (5-HT_1A, 5-HT₄, and 5-HT₆), and GI activity (5-HT₃, 5-HT₄, and 5-HT₇). Serotonergic compounds either currently licensed or being clinically tested for the treatment of disorders related to these functions include the following: lorcaserin (5-HT_2C agonist; obesity), buspirone (5-HT_1A partial agonist; anxiety disorders), vilazodone (combined SSRI and 5-HT_1A partial agonist; anxiety disorders), idalopirdine (5-HT₆ antagonist; Alzheimer’s disease), alosetron (5-HT₃ antagonist; IBS-D), and prucalopride (5-HT₄ agonist; IBS-C).