NPP Exam 1 Review Ch.6 Serotonin

What amino acid is serotonin synthesized from?

Tryptophan (essential)

How can serotonin synthesis be stimulated?

By using large doses of tryptophan

What is the first step of serotonin synthesis?

1. Tryptophan hydroxylase (TPH) converts tryptophan to 5-hydroxytryptophan (5-HTP)

What is the second step of serotonin synthesis?

2. Aromatic amino acid decarboxylase (AADC) converts 5-HTP to 5-HT (serotonin)

What is the rate limiting step of serotonin synthesis?

Tryptophan to 5-HTP conversion

How can we manipulate tryptophan?

Administering PCPA

What does PCPA do?

Blocks 5-HT synthesis by irreversibly inhibiting TPH

How does tryptophan relate to your diet?

Tryptophan from diet can cross the BBB, and thus augment serotonin (5HT)

What happens if you inhibit AADC?

There would be an L-DOPA buildup, no serotonin or dopamine because this enzyme is also needed for catecholamine synthesis

How is serotonin stored?

packaged in vesicles by VMAT

How can VMAT be blocked?

Reserpine

What happens to serotonin is we use reserpine?

it won't make it to vesicles & get broken down by MAO; leads to depression

How is serotonin released?

action potential -> Ca influx -> exocytosis

What are some drugs that affect 5-HT release?

Amphetamines and MDMA

What happens at low doses of MDMA?

increases monoamine release

What happens at high doses of MDMA?

Depletion of 5-HT release, and significant neuropsychiatric impairment

What is SERT?

serotonin reuptake transporter;

removes 5-HT from synaptic cleft

What are SSRIs?

Drugs that block SERT, and thus increase 5-HT actions because it cannot be removed from the synaptic cleft

What is a typical example of an SSRI?

fluoxetine (prozac)

What happens to mutant mice lacking SERT?

They exhibit behavioral, physiological, and psychological abnormalities that are associated to the chronic augmentation of serotonergic activity

What is serotonin catalyzed by?

MAO-A found in neurons and astrocytes

What does serotonin catalysis yield?

5-HIAA

Why are 5-HIAA levels important for clinical diagnosis?

It tells doctors about overall activity of CNS serotonergic neurons

Where do serotonin neurons originate?

In the Raphe nuclei

- Dorsal Raphe nucleus

- Median raphe nucleus

Where are serotonergic fibers particularly dense?

at the cortical surface and the deep layers of the hippocampus

What are the functions of the dorsal raphe nucleus (DRN) for stress and emotions?

The DRN provides the majority of serotonergic input to regions of the limbic system such as the PFC and the hippocampus (HPC)

How does the DRN function for sleep?

During slow-wave sleep, 5-HT neurons slow down their activity

During REM sleep, 5-HT neurons are almost completely shut down

How many serotonergic receptors are there?

At least 14 5-HT

Are serotonergic receptors metabotropic or ionotropic?

Metabotropic

Where are 5-HT1A receptors largely concentrated?

in the HPC and amygdala

Do 5-HT1A receptors inhibit or stimulate adenylyl cyclase?

Inhibits therefore inhibits cAMP

What channel do 5-HT1A receptors stimulate?

K+ channels therefore hyperpolarizes and decreases action potentials

Where are 5-HT2A receptors largely concentrated?

in the cortex

What do 5-HT2A receptors stimulate?

the phosphoinositide second messenger system

What channel do 5-HT2A receptors stimulate?

Ca2+ levels in post synaptic cells and also activates protein kinase C (PKC)

stimulates IP3

What G protein does the phosphoinositide second messenger system use?

GQ proteins

What does the Tph2 gene do?

Tph2 gene knockout (KO) completely eliminates 5-HT from the brain

What is the most common effect of eliminating brain 5-HT?

A large increase in aggressive behavior

What is the serotonin deficiency hypothesis of agression?

low 5-HT signaling into the brain areas involved in aggression produces hyper-aggressiveness

What are other alterations of Tph2-KO mice?

- more impulsivity, less compulsive, and less anxious

- poor communication & social behaviors, more negligent

What type of drug would you use to treat obesity?

- A selective 5-HT2C agonist such as locaserin

- 5-HT1B agonists and 5-HT6 antagonists also produce hypophagia

What is the main serotonin receptor involved with anxiety?

5-HT1A

What happens if you activate 5-HT1A in the hippocampus for spatial learning?

Improves memory formation

What happens if you activate 5-HT1A in the hippocampus for Contextual Fear learning?

impairs memory formation