Serotonin - Lecture 20

Front 1

Serotonin is under which class of monoamines?

Back 1

Indolamines

Front 2

What is serotonin synthesized from?

Back 2

A dietary precursor called tryptophan, an amino acid.

Front 3

What is the rate limiting step in serotonin synthesis? That is, what is unique for serotonergic neurons?

Back 3

Tryptophan hydroxylase

Front 4

What step is common to monoamines?

Back 4

AADC - aromatic L-amino acid decarboxylase

Front 5

What degrades serotonin?

Back 5

MAO-A (Monoamine oxidase-A)

Front 6

Provide all of the steps for the synthesis and degradation of serotonin.

Back 6

Synthesized from L-Tryptophan by tryptophan hydroxylase into 5-HTP (L-5-hydroxytryptophan) which is converted into 5-HT or serotonin by AADC (aromatic L-amino acid decarboxylase). Serotonin is degraded by monoamine oxidase-A

Front 7

Does turkey increase brain levels of tryptophan? Why or why not?

Back 7

NO - turkey has low levels of tryptophan and competes with other amino acids to cross the blood brain barrier. You are more likely to become tired by eating lots of carbohydrates because this produces insulin which signals amino acid uptake from blood into cells but does not affect tryptophan. The result is a ratio of high tryptophan to low other amino acids that can now compete successfully to cross the BBB, synthesize into serotonin and be converted into melatonin.

Front 8

What transporter is unique to serotonin?

Back 8

5-HT transporter (5-HTT or SERT)

Front 9

What allows vesicular transport of serotonin?

Back 9

VMAT2, which is common to both serotonin and catecholamines.

Front 10

What does vesicular storage of serotonin protect this NT from?

Back 10

Breakdown by monoamine oxidase-A in the axon terminal.

Front 11

Rostral Raphe

Back 11

Consists of Dorsal and Median Raphe - ascending projection that consists of B6,7,and 8

Front 12

Caudal Raphe

Back 12

Descending projections directly to motor neurons and sympathetic nervous system - consists of B1-4

Front 13

Dual ascending 5-HT projections (rostral raphe) are located in which part of the brain?

Back 13

They innervate the forebrain structures.

Front 14

Compare dorsal and medial raphe

Back 14

Both (D & M fibers) are the site where projections originate from. They are morphologically distinct; dorsal raphe projections are more diffuse. They both have partially overlapping projection fields and varying degrees of 5-HTT expression (lower in D fibers). Correlated to susceptibility to MDMA neurotoxicity and perhaps indicates site of action of SSRI antidepressants.

Front 15

Serotonin and repetitive movements

Back 15

Increases in 200-500% in firing during repetitive movements such as chewing, licking, grooming. Direct application can increase amplitude of simple jaw reflex and increase the rate of repetitive locomotion such as swimming movements.

Front 16

What is serotonin activity like during rest and during activity?

Back 16

During rest, it is like regular, clock-like firing at low rates. During activity, it increases 10-30%.

Front 17

What are two experimental methods of 5-HT depletion? (One for animals and one for humans)

Back 17

Animals - 5,7 DHT - a neurotoxin that degrades serotonergic terminals and cell bodies. It can be applied to specific regions to target knockouts.
Humans - ATD (acute tryptophan depletion) A cocktail of large, neutral amino acids that compete with tryptophan for entry into the brain. It is transient (~few hours) and reversible

Front 18

How can 5-HT application stop escape responses?

Back 18

In descending 5-HT systems, the application of serotonin can stop escape responses evoked by stimulation of the PAG.

Front 19

How can serotonin decrease activity in the amygdala and its role with fear?

Back 19

If you give humans ATD - there is a decreased amygdala response to fear.

Front 20

What role does 5,7 DHT have in animal's amygdala?

Back 20

Injection of this into the amygdala reduces expression of anxiety in animal models such as the conflict test, where thirsty animals receive occasional shocks when drinking.

Front 21

What role does 5-HT have with punishment?

Back 21

In people who have lowered 5-HT levels, there is enhanced sensitivity to punishment. In the experiment of predicting reward and punishment, people with lowered 5-HT levels had a lower error rate for punishment, but not reward.

Front 22

5-HT1A receptors

Back 22

Have dual inhibitory functions. They are Gi-coupled (inhibits AC, hyperpolarizes the cell by opening K+ channels)

Front 23

5-HT1A in raphe

Back 23

Somatodendritic autoreceptor that produces feedback inhibition (a decreased firing rate of 5-HT neurons)

Front 24

5-HT1A in forebrain projection regions

Back 24

Postsynaptic receptor - inhibits neuronal firing

Front 25

5-HT1B receptors

Back 25

Located in different regions on the neuron. They are also Gi-coupled receptors

Front 26

5-HT1B on axon terminals

Back 26

terminal autoreceptors that produce feedback inhibition (decreases 5-HT release in projection regions)

Front 27

5-HT1B on non-5-HT neurons

Back 27

Presynaptic heteroreceptors that inhibits release of different NTs (such as GABA)

Front 28

Postsynaptic 5-HT2A receptors

Back 28

Gq-coupled -> stimulates phospholipase C. Highest expression on glutamatergic pyramidal neurons (but also on GABAergic interneurons).

Front 29

LSD and Clozapine (atypical antipsychotic)

Back 29

LSD - 5-HT2A agonist
Clozapine - 5-HT2A antagonist

Front 30

Distribution of 5-HT receptors in the human brain

Back 30

Different 5-HT receptors have unique distribution patterns in the brain.

Front 31

5-HT3 receptors

Back 31

Only ionotropic 5-HT receptors. Pass Na+/Ca2+ ions. Play a possible role in anxiety.

Front 32

Palonosetron

Back 32

Serotonin 5-HT3 receptor antagonist used in chemotherapy, which blocks nausea and vomiting

Front 33

SSRI's

Back 33

Major class of antidepressants also used in treatment of anxiety disorders. They inhibit 5-HTT and lead to increased 5-HT levels in the synapse. Effects can take weeks.

Front 34

Pindolol

Back 34

A 5-HT1A antagonist that enhances and speeds up SSRI action.

Front 35

SSREs

Back 35

Reuptake enhancers that function as antidepressants - effects are immediate.

Front 36

Genetic polymorphism in the 5-HTT gene

Back 36

Alters levels of 5-HTT transcription. Homozygotes for the short allele have lower reuptake and show increased incidence of depression after stressful events. Leads to lower levels of 5-HT perhaps due to long term adaptations. The actual coding sequence is the same, difference is in the length of a repetitive upstream promoter.