Serotonin and Dopamine Flashcards
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
- tyrosine => L-DOPA via tyrosine hydroxylase RLE
- L-DOPA => dopamine via dopamine decarboxylase
* dopamine canNOT cross BBB*
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
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
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
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
What is the role of the 5-HT transporter?
reuptake of 5-HT from the nerve terminal
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
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
Describe the following for the use of SSRIs:
- MOA
- effects
- use
- side effects
- contraindications
- prototype drugs
MOA
- prevent reuptake at the axon terminal
EFFECTS
- reuptake inhibition causes an increase in serotonin in the presynaptic cleft
- initially, there is continued inhibition of the post-synaptic serotonin producing neuron because of continued activation of 5-HT1a inhibition
- 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
- 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
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
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)
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
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
List the 4 dopaminergic pathways. Indicate where excess/deficit dopamine occurs and what conditions it can lead to.
- mesolimbic (VTA to limbic)
=> excess DA leads to psychosis - mesocortical (VTA to prefrontal cortex)
=> deficit DA leads to schizophrenia and lack of motivation - tuberoinfundibular pathway (arcuate nucleus of hypothalamus to median eminence of the pituitary)
=> deficit DA leads to parkinson’s - chemotrigger zone (brainstem)
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
