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Flashcards in Serotonin and Dopamine Deck (22):
1

Describe the major features of serotonin and dopamine neurotransmission.

SEROTONIN
1. L-tryptophan => 5-HTP via tryptophan hydroxylase RLE
=> tryptophan is NOT synthesized by the body; essential AA
=> TH is not normally saturated, thus increasing dietary intake of tryptophan can increase 5-HTP production
=> 5-HTP is an OTC nutraceutical used to treat depression
2. 5-HTP => serotonin
3. serotonin => 5-HIAA (inactive excreted metabolite)

DOPAMINE
1. tyrosine => L-DOPA via tyrosine hydroxylase RLE
2. L-DOPA => dopamine via dopamine decarboxylase
*dopamine canNOT cross BBB*

2

Describe how tryptophan manipulations are thought to affect brain function.

- requires appropriate ratio of W to other AAs b/c W competes with other neutral AAs to cross the BBB
- common foods = whole milk, dried prunes, semi-sweet chocolate

3

Where on the neurons are each 5-HT1 receptor found?

5-HT1a
- found on both pre- and post-synaptic
- on the pre-synaptic neuron, it is found on the soma/dendrites to act as an autoreceptor to limit AP generation
- on the post-synaptic neuron, it is found on the synaptic membrane to receive signals

5-HT1b
- found on both pre- and post-synaptic
- pre-synaptic receptors are found on the axon terminal to inhibit phosphorylation of calcium channels (no cAMP => no PKA) => inhibits serotonin release

5-HT1d
- only found on post-synaptic neurons

4

Describe the following for each serotonin receptor family
- MOA
- location on the neuron

5-HT1a, b, d
- MOA => Gi => inhibits NT release and activates K channels
- 1a = presynaptic cell body and postsynaptic membrane
- 1b = presynaptic nerve terminal and postsynaptic membrane
- 1d = postsynaptic only

5-HT2a, b, c
- MOA = Gq => PLC => IP3/DAG => Ca2+
- post-synaptic

5-HT3
- MOA = ligand gated cation influx when activated by SE
- post-synaptic

5-HT4
- MOA = Gas => cAMP => PKA
- post-synaptic

5

Describe the following for each serotonin receptor family:
- location in the body
- effects

5-HT1a
- cortex, hypothalamus => mood and cognitive function
- Raphe nuclei => inhibit 5-HT release

5-HT1d
- cerebral VSM nerve terminal => inhibit NT release

5-HT2a/c
- striatum => hallucinations
- frontal cortex => inhibit DA release

5-HT3
- enteric chromaffin cells => gut motility
- area postrema/esmetic center => N/V

5-HT4
- myenteric plexus => gut motility

6

What is the role of the 5-HT transporter?

reuptake of 5-HT from the nerve terminal

7

Describe the following for buspirone:
- MOA
- effects
- use
- side effects

MOA
- partial agonist for 5-HT1a receptors located on the post-synaptic receptors in the cortex

EFFECTS
- INHIBIT the INHIBITORY activity of 5-HT1 => ACTIVATE serotonin release => more endogenous serotonin

USE
- GAD
- depression (when used in conjunction with SSRIs)

SIDE EFFECTS
- anxiety, drowsiness, nausea
- associated with initial suppression of endogenous serotonin release before the receptor has become desensitized

8

Describe the following for sumatriptan:
- MOA
- effects
- use
- side effects
- contraindications

MOA
- 5-HT1d agonist

EFFECTS
- inhibits release of nociceptive and inflammatory NTs (CGRP, NKA, and substance P)
- activates MLCK => cerebrovascular vasoconstriction

USE
- migraines

SIDE EFFECTS
- cerebrovascular vasoconstriction

CONTRAINDICATIONS
- coronary artery disease

9

Describe the following for the use of SSRIs:
- MOA
- effects
- use
- side effects
- contraindications
- prototype drugs

MOA
- prevent reuptake at the axon terminal

EFFECTS
1. reuptake inhibition causes an increase in serotonin in the presynaptic cleft
2. initially, there is continued inhibition of the post-synaptic serotonin producing neuron because of continued activation of 5-HT1a inhibition
3. 2-4 weeks later (time it takes for anti-depressants to start working, there has been a downregulation of 5-HT1a because of all the serotonin activation
4. less 5-HT1a receptors => less inhibition => more serotonin release => antidepressive effects

USE
- depression
- anxiety from PTSD, OCD

SIDE EFFECTS
- sexual dysfunction
- insomnia
- due to enhanced activation of other receptors

CONTRAINDICATIONS
- pts taking MAOIs => enhance effects of serotonin since it is not being broken down to its inactive metabolite 5-HIAA
- can lead to serotonin-syndrome (hyperthermia, muscle tremors, twitching, agitation, arrhythmia, seizure)

PROTOTYPE DRUGS
- fluoxetine
- sertraline

10

Describe the following for the therapeutic use of SARIs:
- MOA
- effects
- use
- side effects
- contraindications
- prototype drugs.

MOA
- blocks serotonin reuptake
- blocks 5-HT2a and 5-HT2c

EFFECTS
- increased serotonin in the synapse => increased production and release of serotonin
- block 5-HT2a => block alertness
- block 5-HT2c => block sexual behavior and anxiety

USE
- depression (rarely used for this anymore; in combination with SSRIs)
- anxiety
- insomnia w/o depression

SIDE EFFECTS
- drowsiness

CONTRAINDICATIONS
- black box warning for suicidality in young adults

DRUG
- trazadone

11

Describe the following for risperidone:
- MOA
- effects
- use
- side effects

MOA
- 5-HT2a antagonist
- blocks D2 and D3

EFFECTS
- reduces DA release in mesolimbic (too high in psychosis)
- increases DA release in mesocortical (too low in psychosis)

USE
- anti-psychotic
- schizophrenia
- manic episodes of bipolar disorder

SIDE EFFECTS
- weight gain
- akathisia (constant need to move)

12

Describe the following for ondansetron:
- MOA
- effects
- use
- side effects
- notes

MOA
- 5-HT3 antagonist

EFFECTS
- block 5-HT3 => block serotonin release on vagal afferents => block activation of area postrema and emetic center => inhibit N/V

USE
- prevent N/V in chemotherapy patients

SIDE EFFECTS
- few
- well tolerated

NOTES
- 90% of serotonin release occurs in the gut from the enterochromaffin cells
- acts on vagal efferents to induce N/V in response to detection of a toxin in the gut

13

Describe the following for metoclopramide:
- MOA
- effects
- use
- side effects
- notes

MOA
- dopamine antagonist
- 5-HT4 agonist

EFFECTS
- promotes gastric motility by increases activity of IPAN

USE
- short term stimulation of gastric motility in diabetics and post-surgical patients

SIDE EFFECTS
- dopamine agonist effects

NOTES
- 5-HT4 => serotonin => intrinsic primary afferent neurons (IPAN) => ACh => longitudinal and circular gut muscles

14

List the 4 dopaminergic pathways. Indicate where excess/deficit dopamine occurs and what conditions it can lead to.

1. mesolimbic (VTA to limbic)
=> excess DA leads to psychosis

2. mesocortical (VTA to prefrontal cortex)
=> deficit DA leads to schizophrenia and lack of motivation

3. tuberoinfundibular pathway (arcuate nucleus of hypothalamus to median eminence of the pituitary)
=> deficit DA leads to parkinson's

4. chemotrigger zone (brainstem)

15

Describe the MOA and members of the D1 receptor family.

MOA
- Gas => cAMP => increase DA release

FAMILY
- D1 = frontal cortex, arcuate nucleus, hypothalamus
- D5 = hypothalamus, striatum

ACTIONS
- renal and splanchnic vasodilation

16

Describe the MOA and members of the D2 receptor family.

MOA
- Gi => decreased cAMP
- activates K channels
- decreased voltage gated Ca channels

FAMILY
- D2 = striatum, pit
- D3 = VTA
- D4 = hypo, amygdala, hippo

17

Describe the following for the therapeutic use of L-DOPA:
- MOA
- effects
- use
- side effects
- adjunctive therapy

MOA
- precursor loading

EFFECTS
- increased synthesis of dopamine, norepinephrine, epinephrine in the CNS and PNS
- crosses BBB

USE
- parkinson's

SIDE EFFECTS
- limbic = hallucinations
- dyskinesia
can be alleviated with reduced doses and cocktail drugs

ADJUNCTIVE THERAPY
- carbidopa blocks dopamine carboxylase to prevent L-DOPA => dopamine
- cannot cross BBB so reduces toxic side effects in the periphery to allow more L-DOPA to enter the brain rather than be metabolized in the gut

18

Describe the following for bromocriptine:
- MOA
- effects
- use
- side effects

MOA
- D2 receptor agonist in basal ganglia

EFFECTS
- reduces oxidative damage in dopaminergic cells
- increased dopamine in system

USE
- parkinson's

SIDE EFFECTS
- valvular fibrosis with long-term use
- decreased impulse control leading to atypical risky behaviors

19

Describe the following for selegiline:
- MOA
- effects
- use
- side effects
- notes

MOA
- MAO-b inhibitor

EFFECTS
- selective for one type of MAO

USE
- parkinson's (low dose)
- depression (high dose)

SIDE EFFECTS
- dizziness due to hypotension (low dose)
- hypertension and serotonin syndrome (high dose)
- dry mouth due to increased sympathetic activity

NOTES
- doesn't require strict monitoring of dietary tyramine since it is selective
- but should be mindful at higher doses

20

Describe the following for tolcapone:
- MOA
- effects
- use
- side effects

MOA
- COMT inhibitor

EFFECTS
- prolongs L-DOPA half-life
- decreases "off time"
- able to reduce dose needed of L-DOPA

USE
- parkinson's in conjunction with L-DOPA

SIDE EFFECTS
- oscillations in motor function due to off time
- excess dopamine effects: dyskinesia, hallucinations, nausa

21

Describe the following for haloperidol:
- MOA
- use
- side effects

MOA
- D2 receptor antagonist => increases DA

USE
- antipsychotics

SIDE EFFECTS
- extra motor movement
- akathisia, tics

22

Describe the following for methylphenidate: (RECALL)
- MOA
- effects
- use
- side effects

MOA
- DE and NE reuptake inhibitor

USE
- ADHD

SIDE EFFECTS
- tachycardia

CONTRAINDICATIONS
- arrhythmia
- HTN
- TCAs (further exacerbate concentrations of catecholamines)