lecture 11 LOs Flashcards
where are serotonergic neurons in the CNS found
along the midline of the brain stem associated with the raphe nuclei
where else does serotonin exist (besides the raphe nuclues)
the gut
is serotonin a monoamine
yes, similar to both DA and NE
what is the molecular type of serotonin
indolamine
what is serotonin synthesized from
the amino acid tryptophan
what are the steps of the synthesis of serotonin
tryptophan hydroxylase converts tryptophan to 5-hydroxyl-tryptophan (5-HTP) (rate limiting step)
aromatic amino acid decarboxylase (AADC) converts 5-HTP to serotonin
where can tryptophan be found
only in serotonergic neurons
what does para-chlorophenylalnine (PCPA) do
irreversibly inhibits tryptophan hydroxylase to block serotonin synthesis
what stimulates serotonin synthesis
administration of large doses of precursor (either tryptophan or 5-HTP)
how easily does tryptophan get across the blood brain barrier
it competes with other amino acids for transport across the BBB
the ratio of tryptophan determines the stimulation of serotonin synthesis
how can the levels of serotonin in humans be temporarily decreased
giving an amino acid ‘cocktail’ without the tryptophan in it
what does the tryptophan reducing cocktail do (how does it work?)
it decreases the concentration of tryptophan which decreases the amount of serotonin that can be made
it stimulates synthesis of proteins in the liver which also reduces levels of plasma tryptophan
what does reducing tryptophan through the cocktail result in
reappearance of symptoms in previously depressed patients
behavioural changes like increased impulsivity in healthy subjects
what transports serotonin into vesicles
VMAT2
what is VMAT2 sensitive to
reserpine
what do serotonin autoreceptors on presynaptic terminals do
inhibit release
what do somatodendritic autoreceptors (on raphe central bodies) do to serotonin neurons
slows the firing rates of them
after release, how is serotonin removed from the synapse
reuptake by the serotonin transporter (SERT)
how is the breakdown of serotonin catalyzed
by MAO (mono amine oxidase) to make 5-HIAA
what 5-HIAA used as
a measure in the CSF for the activity of serotonin neurons
what does fenfluramine do
enhances serotonin release via amphetamine like mechanisms
supresses appetite
what does MDMA do
enhance serotonin release via amphetamine like mechanisms
low controlled doses can be beneficial in PTSD
what does MDMA work on
DAT and NET but higher affinity for SERT
what do SSRIs like fluoxetine do
selective serotonin reuptake inhibitor
how many serotonin receptors are there
at least 14
where does the serotonin receptor 5-HT1A reside
postsynaptically: in forebrain regions
somato-dendritic autoreceptor: on the cell bodies in the raphe nucleus. inhibits cAMP and/or increases the opening of K+ channels
what is a serotonin receptor 5-HT1A agonist and antagonist
full agonist: 8-OHDPAT
partial agonist: buspirone
antagonist: WAY-100635
what do serotonin 5-HT1B and 5-HT1D receptors do
serve as presyanptic autoreceptor on serotonin terminal
where is serotonin receptor 5-HT2A found and what does it do
distributed widely in cortex and in striatum/nucleus accumbens
activates phosphoinositide second messenger system (inc ca2+ levels and activates protein kinase C)
what is a serotonin receptor 5-HT2A agonist and antagonist
agonist: DOI. hallucinogenic in humans
antagonist: ketanserin
how to investigate serotonin function in humans
compare CSF levels of 5-HIAA or postmortem 5-HT/5-HIAA levels w behavioural traits or neuropsychiatric disorders
assess responses to SSRIs or receptor agonists/antagonists
correlate psychiatric disorders and genetic polymorphisms of SERT or 5-HT receptors
how to investigate serotonin function in animals
lesion serotonin neurons with selective neurotoxins
genetically engineer KO mice lacking certain serotonin receptors or delete the enzyme that makes serotonin
which serotonin medications and receptors reduce food intake
SSRIs or 5-HT1B or 5-HT2C
how do serotonin medications like SSRIs and serotonin receptors like 5-HT1B or 5-HT2C reduce food intake
reducing amount of food consumer per meal (but not number of meals)
shift food preference away from fatty foods
what do serotonin receptor 5-HT1A agonists do
stimulate somatodendritic autoreceptors which reduces serotonin release, leading to hyperphagia (over eating/lack of satiety)
what can serotonin receptors do to anxiety
regulate it in opposing manners
how do h-HT1A agonists do to anxiety
reduce it
how do h-HT1A KO mice react to elevated plus maze
increased anxiety
effects of 5-HT1A agonist on reducing anxiety happens where
postsynaptically
activation of other postsynaptic serotonin receptors (with 5-HT2A/2C agonists) does what to anxiety like beh
increases it
what do 5-HT2A/2C KO mice show
reduced anxiety
what is low serotonin activity associated with
increased aggression
what do 5-HT1A/1B agonists do to aggressive beh in mice
decrease it
due to action on post synaptic receptors
depletion of what can cause aggression in humans in lab test
tryptophan
what is an assay for impulsivity in mice
light flahses, rat presses L lever, light does not flash rat presses R lever
during the intertrial, the rat must not press any levers
what do 5-HT selevtive lesions impair
waiting
does this by increse premature responses
what do 5HT2C antagonists do
impair impulsivity
what do 5-HT2C agonists do
reduce impulsivity
