Ch 6: Serotonin

L-tryptophan —tryptophan hydroxylase→ L-5-Hydroxytryptophan —aromatic L-amino acid decarbaylase→ 5-HT

Serotonin Synthesis Pathway

Synthesis regulated by

Enzymic activity and precursor availability

TPH2

Only in serotonergic neurons

TPH1

Non-neuronal cells in gut and pineal gland

Telotristat

TPH inhibitor, does not cross BBB, treats neuroendocrine tumors

PCPA

Blocks 5-HT by inhibiting TPH until brain makes more, irreversible

ATD

Blocks 5-HT by giving large dose of amino acids in a cocktail, impairs cognitive functions

Tryptophan Loading

Administration of pure tryptophan

5-HT Depletion using ATD

Throws depression patients into relapse, but not those with anxiety

Catecholamine Depletion

Throws anxiety patients into relapse, but not those with depression

Kynurenine Synthesis Pathway

Tryptophan —IDO/TDO→ Kynurenine

IDO

Active in brain and immune system cells

TDO

Active in liver

Somato-dendritic Autoreceptors

Inhibit 5-HT release by slowing firing rate of nerve

Reserpine

Depletes 5-HT when not protected by vesicles

5-HT Agonist Drugs

PCPA, Fen-fen, MDMA

Fluoxetine

Increases extracellular 5-HT by interfering with inactivation

DRN and MRN

Important brain structures for serotenergic neurons

5-HT1A

Inhibits adenylyl cyclase, decrease cAMP synthesis, increase K+ channel openings, membrane hyperpolarization

Buspirone

Partial agonist for 5-HT1A

Problem of administrating 5-HT1A antagonist systematically

Both post and autoreceptors are antagonized

5-HT2A

Activates phosphoinositide 2nd messenger system, increases intracellular Ca+

Triptans

5-HT1B agonist for migraines

Lasmiditan

5-HT1F agonist for migraines, decreases activity in pain pathways

Chemotherapy Drugs

Stimulates 5-HT release in the gut which stimulates vagal 5-HT3 receptors, → vomiting

Zofran

5-HT3 antagonist, counteracts nausea/vomiting

Tph2 Knockout Mice

Loss of 5-HT in brain only, mice were more impulsive and had decreased anxiety/social behaviors

Buspirone, Vilazodone

SSRIs that treat anxiety disorders, target 5-HT1A

Postsynaptic 5-HT

Important in regulation of anxiety

5-HT1A Knockout Mice

Had increased anxiety levels

Reactive Aggression

Response to provocation, threat, or frustration

Proactive Aggression

Planned to achieve goal

Serotonin Deficiency Hypothesis of Aggression

Decreased CNS serotenergic activity is associated with hyper-aggressiveness

Sertraline

SSRI that decreases anger and irritability in many psychiatric disorders