Serotonin

History of serotonin

vasotonin: first discovered as a substance that appears in serum when blood clots

vasoconstrictor; removed from blood by passage through the lungs

isolated in 1948 as a complex with creatinine Þ called serotonin

1930s and 40s: Italians discovered enteramine (a gut stimulating factor; acts on smooth muscle)

1950-2: 5-hydroxytryptamine is synthesized and found to have same effects as enteramine and serotonin

5-HT is a biogenic amine in the same family as the catacholamines

it works close to its site of synthesis and release Þ paracrine hormone

1953: serotonin found in brain tissue

1954-64: LSD and hallucinogens found to be similar to serotonin

LSD and cocaine block smooth muscle responses to serotonin
tranquilizers found to lower serotonin levels in the brain

Biodisposition of Serotonin

made from tryptophan in two step process (trp is an essencial amino acid)

active uptake of trp is a prerequisite for synthesis; amount of trp in brain is proportional to the amount synthesised

metabolism to 5-hydroxyindole acetic acid (5-HIAA) via monoamine oxidase (MAO)

excretion in urine 2-10 mg of 5-HIAA per day

further metabolism through aldehyde dehydrogenase and aldehyde reductase

action at receptor sites is terminated by reuptake (Na dependant, carrier mediated)

carrier located in outer membrane of serotanergic axons and platelets

Actions of Serotonin

general: smooth muscle constrictor and CNS moderator but has huge variety of effects

present in most organs with smooth muscle

can stimulate or inhibit smooth muscle and nerves

central neurtransmitter

responses are variable intra- and inter-species

some 5-HT agonists cause release of other substances activating other receptors

i.e. serotonin stimulates epi release so we see effects of epi, but it was mediated by serotonin

some agonists can interact with more than one receptor type

many determinants cause variability of serotonin action

pattern of innervation

route and speed of injection: if inject into pulmony artery it is cleaned out by the lung

aesthetic state: anesthesia may make it impossible for serotonin to have an effect

spontaneous tone: if resting vascular tone is high, serotonin effects may not be noticed

tachyphylaxis: when tests are given at frequent intervals, a diminished response is seen

Ý dose Þ ß response (occurs rapidly)

enterochromaffin cells in GI tract

easiest to ID in GI tract (duodenum)

cells synthesize and store 5-HT; release triggered by ACh, nor epi, increases in intraluminal pressure (full intesine), decreased pH (gastric emptying)

release augmented by mechanical stretching or hypertonic saline

six different receptors Þ release leads to either augmented or inhibited motility

platelets

take up, store, release, but do not synthesize

varying effects:

5-HT_2A receptor Þ accelerated platelet aggregation, vasoconstriction

5-HT₁ receptor Þ EDRF (NO) release Þ vasodilation

net effect is hemostasis and balanced effect in vascular injury

respiratory system

stimulates afferent nerves Þ transient tachypnea (Ý breathing)

bronchoconstriction (effect usually covered up by resting tone)

cardiovascular

classic response is vasoconstriction but variable

may cause release of EDRF, prostaglandins Þ vasodilation

augments vasoconstriction effect of ANGII, histamine

nor epi: serotonin can inhibit release, but augment the effects of nor epi that has already been released

positive ionototropic and chronotropic effects (modulated by stimulation of baro- and chemoreceptors)

CNS

5-HT influences sleep, cognition, sensory perception, motor activity

raphe nuclei of brainstem are main stores, but effects are all over the brain

can be released at synapses and varicosities along axon (diffusion to other targets)

acts as a neurotransmitter and a neuromodulator

behavioral effects:

depletion leads to insomnia; tryptophan accelerates sleep onset; 5-HT is a precursor to melatonin (used as sleep aid)

low 5-HIAA (serotonin metabolite) in CSF associated with violent suicides

loss of serotonin receptors associated with animal aggressiveness and Ý depression

little hard data, but most new antidepressents target serotonin and are very effective

Specific serotonin reuptake inhibitors (Prozac is the big one): acts to Ý serotonin levels

tricyclic antidepressants are the gold standard drugs but are very toxic

5 SSRIs are available; very safe (huge theraputic index); as effective as tricyclics

long halflife (330 hrs); eventually causes a depletion of whole body serotonin Þ difficult to get off SSRIs

side effects: insomnia and aggression from decreased serotonin; transient appetite loss

each SSRI inhibits one or another P450 Þ lots of potential for drug-drug interactions

Receptors

characterization: selective agonist response; blocked by antagonist of high potency and selectivity; agonists of other receptor types are inactive

largest neurotransmitter/receptor family; 14 types cloned; four families

5-HT₁ (G-protein coupled) – vasodilation, in platelets

five members distributed throughout brain
moderate CNS activities and behavior through axodendritic connections
also effects vascular smooth muscle in skull

5-HT₂ (G-protein coupled) – vasoconstriction

mostly found in platelets

acts with phospholipase C Þ IP3 (Ca release) and DAG (activate Protein Kinase C)

2A (prefrontal cortex and platelets); 2B (fundus of stomach); 2C (choroid plexus)

5-HT₃ (ligand-gated ion channel) – gates Na/K

in parasympathetic nerve terminals in GI tract

concentrated in area postrema Þ emetic response (vomitting)

5-HT₄ (G-protein coupled)

distributed throughout body – less specific

in superior and inferior colliculi and hippocampus in CNS

evokes intestinal secretion and peristalsis Þ constipation is problem in elders

activates cAMP

Sumatriptan (works like methysergide without the side effects): very specific for migraine headaches (if it doesn’t work, you probably don’t have a migraine)

potent, selective for 5-HT_1D receptors in carotid A-V anastomoses Þ increases vascular resistance

little effect on smooth muscle outside the CNS

effect is not dose dependant - narrow window of effectiveness (too much or too little doesn’t work)

Ondansetron – anti-emetic – used to counteract action of chemotherapeutic drug cispantin, which causes emesis

vomiting center has receptors for dopamine, opiates, serotonin (chemoreceptor trigger zone - CTZ)

inhibition of any of these can give emetic control

vomiting is a major side effect of chemotherapy

chemo causes damage to gut Þ serotonin release Þ activation of S3 receptors on visceral afferent fibers Þ CNS (CTZ)

ondansetron works on the serotonin receptors in the CTZ

much safer and more effective than current anti-emetic formulations