Serotonin

What is the formal name of serotonin?

5-hydroxytryptamine (5-HT)

What is the precursor to serotonin?

Tryptophan (essential amino acid)

What is the rate-limiting enzyme in serotonin synthesis?

Tryptophan hydroxylase (TPH)

How does a high-protein meal affect tryptophan entry to the brain?

It decreases tryptophan crossing the BBB due to competition with other amino acids

How does a low-protein/high-carb meal affect tryptophan entry to the brain?

It increases tryptophan crossing the BBB due to insulin effects

What happens when tryptophan levels are low?

Impaired memory of verbal info, increased negative cognitive bias, reduced sleep quality/duration

What pathway does most tryptophan go through instead of serotonin synthesis?

Kynurenine pathway

What enzymes convert tryptophan to kynurenine under stress/inflammation and control how much tryptophan gets converted to kynurenine

IDO and TDO

How is serotonin stored in neurons?

In vesicles via VMAT2 to protect it from degradation

What controls the release of serotonin from neurons?

Autoreceptors

What is the primary way serotonin is removed from the synapse?

Reuptake by the serotonin transporter (SERT)

Which type of drugs block SERT to increase serotonin in the synapse? Give two examples.

SSRIs (Selective Serotonin Reuptake Inhibitors) such as Fluoxetine/Prozac or Sertraline/Zoloft

Name two other substances that interact with SERT.

Cocaine and MDMA

What is the secondary method of serotonin removal?

Enzymatic degradation by MAO and aldehyde dehydrogenase

What is the main metabolite produced when serotonin is broken down?

5-hydroxyindoleacetic acid (5-HIAA)

How is 5-HIAA used in research?

Measured in brain or CSF to indicate serotonin activity

What was the first SSRI developed?

Fluoxetine (Prozac)

What does “entactogen” mean? And what recreational drug is considered this?

A drug that promotes social closeness and empathy; MDMA

What are some therapeutic uses of MDMA today?

Treatment for PTSD and potentially alcohol use disorder

What can high doses of MDMA do to serotonin neurons?

Cause long-lasting loss of serotonin and serotonergic axons

Where are most serotonin neurons located in the brain? And what are the two main parts of that brain area

In the raphe nuclei of the brainstem; Dorsal Raphe Nucleus (DRN) and Median Raphe Nucleus (MRN)

Name some brain regions that receive serotonin fibers from the raphe nuclei.

Prefrontal cortex, striatum, nucleus accumbens, thalamus, hypothalamus, limbic system

Is serotonin distributed equally across the brain?

No, it is denser in some regions, especially the cortex Layer I

What functions might dense cortical serotonin influence?

Mood, cognition, dendritic processing, and neuronal communication

How many serotonin receptors are known, and which is ionotropic?

14 known; 5HT3 is the only ionotropic receptor

Where are 5HT1A receptors found and what do they do?

In Postsynaptic neurons in the Hippocampus, septum, amygdala, dorsal raphe; They decrease cAMP and open K+ channels → leads to hyperpolarization (less firing)

5HT1A can act as ____ auto receptors in the DRN/MRN which can do what to serotonin neuron during?

somatodendritic/// Suppressing serotonin neuron firing and possibly decreasing serotonin synthesis

Which drug is a partial agonist at 5HT1A receptors?

Buspirone (anxiolytic)

Where are 5HT2A receptors found and what are they associated with?

Cortex, striatum, nucleus accumbens; hallucinogenic effects, schizophrenia

What is the difference between somatodendritic and presynaptic autoreceptors?

Somatodendritic (on soma/dendrites) suppress firing; presynaptic (on axon terminals) decrease serotonin release

Which signaling pathway does 5HT2A activate?

Phosphoinositide system → increases Ca²⁺ → activates PKC

Which hallucinogenic drug strongly stimulates 5HT2A?

LSD

How can inverse agonists of 5HT2A help clinically?

They reduce receptor activity and may help treat schizophrenia

Which 5HT receptors are targeted by triptans for migraine treatment?

5HT1B and 5HT1D (also 5HT1F by lasmiditan)

How do triptans relieve migraine pain?

By activating 5HT1B/1D presynaptic receptors on perivascular nerve fibers → constriction of capillaries → reduced pain

What behavior is linked to increased 5HT2 receptors in patients with major depression?

Suicidal or impulsive behavior

Which side effect is associated with 5HT2 receptor overstimulation by SSRIs?

Sexual dysfunction

Where are 5HT3 receptors located?

Peripheral terminals of the vagus nerve

How do 5HT3 antagonists like ondansetron (Zofran ) work?

Block 5HT3 receptors → prevent nausea and vomiting (especially from chemotherapy)

what are the 2 major types of serotonin auto receptors? and where are they located

Somatodendritic autoreceptors found on cell body (soma) and dendrites and presynaptic autoreceptors found on axons/axon terminals

What is the primary function of somatodendritic autoreceptors?

Suppress neuron firing and may reduce serotonin synthesis

Which serotonin receptor subtype acts as a somatodendritic autoreceptor?

5HT1A

What is the primary function of presynaptic autoreceptors?

Decrease serotonin release (and possibly synthesis) at the synapse

What gene’s polymorphisms are linked to depression?

SERT (serotonin transporter)

What serotonin metabolite is linked to aggression?

5-HIAA

How does serotonin affect feeding behavior?

Modulates appetite and satiety

Which receptors mediate anxiolytic effects?

Postsynaptic 5HT1A receptors

Which drugs are used to treat anxiety via the serotonin system?

SSRIs and 5HT1A partial agonists (Buspirone)

What happens if 5HT1A receptors are knocked out in mice?

Inc anxiety

What brain regions are involved in aggression?

BNST (bed nucleus of the stria terminalis) and amygdala

What metabolite is linked to aggression levels? Does low or high levels lead to more aggression?

5-HIAA (low levels → high aggression)

What is the Serotonin Deficiency Hypothesis of Aggression?

Low serotonin activity is associated with high levels of aggression

How can aggression be reduced pharmacologically?

SSRIs increase serotonin → reduce aggression

Define aggression, give examples

behavior intended to cause physical or psychological harm or pain to the victim. Can be reactive or proactive; can include: •predatory, antipredator, dominance, sex-related, maternal, territorial, defensive, and irritable aggression

What is the effect of enhancing serotonin (5HT) activity on food intake and body weight?

It decreases food intake and body weight.

Which drug increases serotonin to lower appetite but has severe cardiac side effects?

Fenfluramine

Which brain region is a key hub for feeding regulation?

The arcuate nucleus of the hypothalamus

What do POMC+ neurons secrete and what is their effect on appetite?

They secrete α-melanocyte stimulating hormone (α-MSH), which binds to melanocortin receptors and suppresses appetite (anorexigenic)

What do NPY/AgRP neurons do?

They stimulate appetite (orexigenic) by inhibiting melanocortin receptors

Where do POMC and NPY/AgRP neurons project to in order to regulate feeding?

They project to the paraventricular nucleus (PVN) onto melanocortin receptor neurons.

What is the overall role of α-MSH vs AgRP in feeding behavior?

α-MSH → anorexigenic (suppress appetite)
AgRP → orexigenic (stimulate appetite)

Where is most serotonin in the body located?

In the gut (90–95%) in the enteric nervous system

What triggers serotonin release in the gut? and what is its function?

Food entering the gastrointestinal tract; Stimulates peristalsis and release of fluids and hormones to aid digestion

Which enzyme produces serotonin in the gut versus the brain?

Gut: TPH1, Brain: TPH2

How does altered gut serotonin contribute to IBS, and what are the treatments for IBS-D and IBS-C?

Altered 5HT activity leads to IBS symptoms

• IBS-D (diarrhea): excessive serotonin leads to too-fast peristalsis → treatment: 5HT3 antagonists to slow gut movement

• IBS-C (constipation): low serotonin leads to slow peristalsis → treatment: 5HT4 or 5HT7 agonists to increase transit

The gut-brain axis is a ___ connection between the gut and brain via the __ nerve

bidirectional // vagus nerve

Which behaviors and mood traits are linked to serotonin levels?

Impulsivity, irritability, depression, and high anxiety

Other than depression, SSRI’s are used to treat…

anxiety and OCD

How do newer antipsychotic drugs work in relation to serotonin and dopamine?

They block 5HT2A receptors (the same receptor LSD stimulates, which can cause hallucinations) and block D2 dopamine receptors, helping to reduce psychotic symptoms.

Name 3 common SSRIs.

Fluoxetine (Prozac), Sertraline (Zoloft), Escitalopram (Lexapro)

How does mirtazapine work? and what kind of drug is it

An atypical ADT; Blocks α2-adrenergic autoreceptors (increases NE and 5HT), blocks 5HT2 receptors, H1, and muscarinic receptors; does not block reuptake

What is the mechanism of SNRIs?

Block reuptake of both serotonin and norepinephrine → increase levels of both neurotransmitters in the synapse

Give two examples of SNRIs.

Venlafaxine (Effexor), Duloxetine (Cymbalta)

What is serotonin syndrome?

A potentially fatal condition caused by too much serotonin in the CNS, often from drug interactions

Name common symptoms of serotonin syndrome.

Delirium, confusion, hypomania, hyperthermia, shivering

Which drugs are most critical for causing serotonin syndrome?

Irreversible MAOIs (phenelzine/Nardil, tranylcypromine/Parnate), SSRIs, tryptophan, Demerol

What is the safe waiting period between stopping an MAOI and starting an SSRI?

2 weeks (except Prozac → wait 5 weeks before starting MAOI)