Serotonin Synthesis Flashcards
Cascade of events for precursors-who?
L-tryptophan is the main precursor
Rate-limiting enzyme
TPH (tryptophan hydroxylase)-not normally saturated so tryptophan intake can influence 5-HT production
5-HTP
OTC nutraceutical used for depression
What is the active NT?
Serotonin (5-HT)
5-HTP –> 5-HT, enzyme?
5-HT decarboxylase
What are the important receptors?
5-HT 1A 5-HT1D 5-HT2A/2C 5-HT3 5-HT4 5-HTtransporter
5-HT 1A effect
in the cortex and hypothalamus affect mood, cognitive fxn, neuro.endo fxn
5-HT 1D Effect
vasoCONSTRICTION on cerebral VSM, inhibition on NT release on certain nerve terminals
5-HT 2A/2C
in striatum and frontal cortex, antagonists that act here can produce hallucinations. Also inhibit dopamine release
5-HT 3
- on enteric chromaffin cells (of the gut)–>stimulate sertonin release through these.
- area postrema
- emetic center-can stimulate vomiting (as defense mech)
- nausea and vomiting of chemo, can play with these receptors
5-HT 4
-myenteric plexus (enteric nervous system)-gut motility via agonists
5-HT transporter
-increase serotonin presence in the synapse to help improve mood
Drug Examples
5-HT 1A-BUSPIRONE 5-HT1D-SUMATRIPTAN 5-HT2A/2C-TRAZODONE, RISPERIDONE 5-HT3-ONDANSETRON 5-HT4-MOSAPRIDE 5-HT transporter-FLUOXETINE, SERTRALINE
5-HT 1A Agonists
numerous 1A receptors…ones in cortex mediate anti-depressant effects
1A: BUSPIRONE
Indications: generalized anxiety disorder; OFF label use: with SSRI for major depression
MOA: unknown, but likely due to activatoin of post-synaptic receptors in cortical regions, partial agonist 1A R
SE:can increase anciety during intial tx, drowsiness (but less than benzos), nausea
1D: SUMATRIPTAN
MOA: inhibition of **inflamm mediator release, cerebrovasoconstriction…coupled to alpha TWO (no systemic effect because its in brain, BUT coronary arteries have some action)
Indication: Prophylactic for migraine
SE: coronary vasoCONSTRICTION
Ci: pt with CAD
What do SSRIs do to 5-HT?
Increases [5-HT] at synapse because they inhibit the uptake which also activates autoreceptors
SSRI: FLUOXETINE and SERTRALINE ppttRV
Indications: depression, PTSD, OCD
MOA:
Ci: serotonin syndrome=excess serotonin..hyperthermia, thermoregulatory receptors in the hypothamlamus that willg et overactivated, mental status changes (can develop seizures-life threatening)
SARI (Serotonin ANTagonist-reuptake inhibitor): TRAZADONE
increase serotonin and block its bad effects, facilitate good effects at 1A
MOA: 2A/2C antagonist + SSRI hypnotic, SSRI, blocks side effects associated with SSRIs
Indication: anxiety, depression (in combination of SSRI)
SE: warning of suicidality in young adults at initiation or treatment (black box-for early pt of tx)
Ci: MAO inhibitors
2nd Gen ANTI-psychotics: RISPERIDONE
targets mesolimbic system
MOA:2A/D2.3 antagonist suppresses DA release in mesolimbic pathway, but increases DA release in mesocortical pathway
Indication: Schizophrenia with psychosis
SE: weight gain, anxiety, akathisia, psychosis with abrupt discontinuation
Where is the majority of serotonin found?
90% is found in enterochromaffin cells of the gut. Release of 5-HT can be activated by various mechs: chemo (..nausea response)
5-HT3 R ANTAgonist Drug: ONDANSETRON
important site: in the gut, stimulate vagal afferents to start firing, will stimulate nausea an vomiting
Indication:chemo induced emesis
MOA:block 3 R
SE:well tolerated :) :) :)
5-HT 4
MOSAPRIDE (not in the US)
CISAPRIDE (discontinued)
MOA: 5-HT4 induced stimulation of ACH release in the myenteric plexus
Indication: gastroparesis
SE: arrythmia (long QT syndrome)***
Dopaminergic System 4 places that are targeted?
- Mesocortical-ventral tegmentum to cortex (reduce in activity, leads to lack of affect in schizo, cant perseve emotional responses in other indivs)
- Mesolimbic-psychotic aspects (delirium, delusions in schizo)
- Nigrostriatal-hypOactive in pt with Parkinson’s
- Chemoreceptor Trigger Zone (also activated with 5-HT)-to stop nausea
