serotonin neurotransmission

where does serotonin come from

• Produced in the raphe nuclei, located along the midline of the brainstem 

• This is major serotonergic system in the brain 

• From there, projections spread widely to cortex, hippocampus, hypothalamus, and spinal cord

what is serotonin

• Produced in the raphe nuclei, located along the midline of the brainstem 

• This is major serotonergic system in the brain 

• From there, projections spread widely to cortex, hippocampus, hypothalamus, and spinal cord

what does serotonin do

• At neuronal level: modulates excitability, can be excitatory (5-HT3) or inhibitory (5-HT1), regulates neurotransmitter release

• At systems level (brain/body): mood regulation, appetite, sleep-wake cycles, pain perception, GI tract motility and vomiting reflex

Pharmacology issue: specificity vs selectivity

• Many xenobiotics designed for one system also affect serotonin receptors

• Example: drugs at the 5-HT3 receptor also interact with: 

  • Injection anesthetics (pentobarbital, propanol)

  • Local anesthetics (cocaine, lidocaine) 

  • Opioids (morphine, hydromorphone)

  • Cannabinoids (Δ9-THC, anandamine) 

  • Antipsychotics (chlorpromazine, clozapine)

• Takeaway: receptor promiscuity = both therapeutic potential and side effects 

pharmaceuticals that target serotonin

1. Antidepressants (SSRIs, SNRIs)

2. Anti-migraine triptans 

3. Antiemetics (5-HT3 antagonists) 

4. Psychedelics (under investigation for psychiatric use)

antidepressants

• Monoamine hypothesis of depression (1960s): 

  • Depression results from insufficient monoamine neurotransmission (esp. Serotonin, norepinephrine)

  • Supported by discovery of SSRIs

  • Main classes: SSRIs and SNRIs

SSRIs

• Fluoxetine (prozac) - since 1980s

• Citalopram (Celexa) - since 1990s

• Escitalopram (Cipralex) - since 2000s

• Mechanism: block serotonin transporter (SERT) → increase serotonin in synapse

SNRIs

• Venlafaxine (effexor) - since 1990s

• Duloxetine (cymbalta) - since 2000s

• Mechanism: block SERT + NET → boost both serotonin and norepinephrine

triptans (anti-migraine drugs)

• Agonists at 5-HT1 receptors 

• Mechanism of relief: 

  • 5-HT1B: vasoconstriction of cerebral blood vessels 

  • 5-HT1D: inhibits trigeminal nerve, reduces neuropeptide release, decreases neurogenic inflammation 

• Ergotamine: old drug, very promiscuous (5-HT, DA, adrenergic receptors). Most forms removed from market, still available in Canada (injection/nasal)

• Sumatriptan, zolmitriptan: selective fro 5-HT1B/aD, multiple formulations (tablet, ODT, injection, nasal)

antibiotics (5-HT3 antagonists)

• Mechanism: block serotonin signaling from enterochromafin cells in GI tract → vagal nerve → vomiting center 

• Normal serotonin release: regulates peristalsis

• Excessive serotonin release: trigger vomiting reflex 

• Drugs: 

  • Ondansetron (1991): first gold standard, still widely used post-chemi or post-surgery 

  • Palonosetron (2017): newer, stronger affinity, used with dexamethasone for chemotherapy