Serotonin

Question 1

Serotonin Synthesis

Answer 1

Regulated by enzymes and precursor availability:

precursor: tryptophan (from diet)

Step 2: rate limiting step: tryptophan hydroxylase converts tryptophan into 5-HTP

• • drug: PCPA - irreversibly inhibits tryptophan hydroxylase
• • Tryptophan hydroxylase is a 5ht cell marker

Step 3: 5HTP –> 5HT by AADC

Question 2

Tryptophan Availability

Answer 2

Need to get from diet – best way is low protein high carb diets, because trypt. competes with other amino acids and peptides to get across the BBB.
Insulin helps trypt get across the BBB in this competition.
Injection of tryptophan in blood DOES increase 5HT in the brain.. but not significantly if you eat it.

Question 3

Serotonin Receptors

Answer 3

Large Family - most metabotropic except 5HT3

5HT1 : most common class.

• 5HT1a = INHIBITORY in hippo, septum, amyg, raphe; post synaptic receptors in cortex, hippo, amyg. –> activates k+ channels and inhibits adenylyl cyclase.
• —-drug: buspirone is a 5HT1a agonist and anit anxiety
• —-genetic deletion of 5HT1a receptor results in increased anxiety-like behavior.
• —-5HT1a mediates axiolytic effects
• —-5HT1a agonist decreased freezing in contextual learning paradigm when administered before testing (no effect AFTER testing so activation produces deficit in ENCODING not consolidation)
• 5HT2a = EXCITATORY - leads to internal calcium release from the ER and activates PKC via phosphoinositide 2nd messenger system.
• —-drug: DOI/LSD = agonists, Ketanserin = antagonsists
• —–5HT2a/c agonists increase anxiety behaviors
• Other Receptors:
• -5HT3 antags = Zofran, relieves nausea from chemo trtmst.
• -5HT1b/d agonists (triptans) constrict blood vessels.

Question 4

Serotonin Breakdown

Answer 4

Only by MAO –> 5ht –.> 5HIAA (can be used as a measure of 5ht activity ‘turnover’)

Question 5

5HT and Hunger

Answer 5

• 5HT2c/1b agonists and 5HT6 antagonists produce hypophagia

- 5HT1a agonist produces hyperphagia (because of the stimulation of somatodendritic 5HT1a auto receptors)

Question 6

5HT and Anxiety/Mood Regulation

Answer 6

-5HT1a mediates axiolytic effects
—> presence or absence of 5HT1a receptors during development alters baseline expression of anxiety behavior as adults.
(deficient 5HT1a during development could produce later anxiety disorders as adults)

• 5HT2a/c agonists increase anxiety behaviors
• –> deletion of 5HT2a/c creates anxiolytic effect

AGGRESSION:

• low 5HT levels correspond with increased aggression in humans
• OPPOSITE for fish! where high 5HT levels correspond with aggression.

Question 7

5HT and Pain

Answer 7

involved in the processing of pain signals at the spinal cord.
-5HT in raphe magnus inhibits pain transmission and produces hypoalgesic (via 5HT1b and 5HT3)

Question 8

5HT and Learning and Memory

Answer 8

Study via contextual fear conditioning task:
–> 5HT1a agonist decreased freezing in contextual learning paradigm when administered before testing (no effect AFTER testing so activation produces deficit in ENCODING not consolidation)
((specifically dorsal hippo 5HT1a))

–> 5HT4 agonists increase L&M - produce excitatory effect on psc. (may facilitate cholinergic transmission)

• -> 5HT6 antagonists facilitate memory of platform location in rats on the MWM, increase novel obj recognition task performance
• —-currently being developed to help Alzheimer’s and schizo symptoms.