NRSC 2270- Serotonin

90-95 of serotonin

in the gut in enterochromaffin cells

other name for serotonin

5HT

is a monoamine in the class of indoleamine

serotonin cannot

cross BBB so it must be made

serotonin pathway

side effect of increased serotonin

stomach upset

types of trp hydroxylase

tph1 and tph2

tph1

gut and elsewhere

tph2

cns

trp competes with large aa

for transport across BBB

ratio between trp and aa competitors determines wheter

serotonin synthesis is stimulated in the brain. elevated levels of serotonin does not mean elevated brain level because trp is not getting to the brain

rat inject

injection of trp raises 5ht levels but high protein diet does not

most proteins contain more competitor aa than trp

increases plasma serotonin levels can be achieved naturally with a high carb low protein diet to push ratio toward increased trp which may not dramtically effect brain levels of 5ht

may be due to insulin ablity to stimulate the uptake amino acids from bloodstrea except for trp

serotonin vesicles

vmat 2

terminal serotonin autoreceptors

1b and 1d

somatodendritic serotonin autoreceptors

1a in raphe nuclei

Sert

serotonin is removed by sert

what catalyzes serotonin

mao-a to 5HIaa

5hiaa

5hydroindoacetic acid, breakdown product of 5ht

• used as indirect measure of the acitivity of serotonergic neurons

5HT

release via indirect agonist

PCA

indirect agonist of serotonin

• depletion of brain serotonin and neurotoxicity

• not in clinical use

fenfluramine

fen phen

• reverses SERT and disrupts vesicular storage. massive release of serotonin which causes vasoconstriction and cardiac events

MDMA

ecstasy, molly

• indirect agonist

• hemostatic agent

• produces strong feelings of empathy and social lubricant.

MDMA has a high affinity to

SERT (lesser extent for NET and DAT)

• may also have direct effects on several 5HT receptors

how does MDMA stimulate serotonin efflux

via sert, mdma stimulates 5ht efflux from synaptic terminals via a reverse transport mechanism and blocking vmat 2

ssri and mdma

• block mdma ability in vitro to bind sert and stimulate 5ht release

• schedule 1 drug

mdma and therapy for ptsd

the treatment may have meaningful advantage and greater compliance over available medications for ptsd

MDMA as a DA neurotoxin

toxic levels of MDMA can cause it to have neurotoxicity effects and developed malignant hyperthermia

• causes reduced 5ht density in the forebrain fibers

sert ko mice

exhibit an array of behavior and phsyioogical abnoramlities resulting from chronic enhancement of serotonergic activity

serotonin syndrome

• severe toxicity associated with different combos of sertonergic drugs

  • combining maoi with OTC meds can cause this toxicitiy

clinical trademarks of serotonin syndrome in humans

cognitive effects, autonomic, somatic effects

cognitive effects

headache, agitation, hypomania, mental confusion, hallucinations, coma

autonomic effects

shivering, sweating, hyperthermia, vasoconstriction, tachycardia, nausea, diarrhea

somatic effects

myoclonus (muscle twitching), hyperreflexia (manifested by clonus), tremor

serotonin syndrome in mice

cell bodies of the serotonic system

dorsal and median raphe nuclei and has proections to the neuronal axis

how many receptors subtypes are for 5HT

14 receptors divided into 7 families

metabotropic (most)

5-HT 1A receptors (GI)

in forebrains mainly hippocampus

post synaptic receptors

raphei nuclei (brain stem)—> somato dendritic autoreceptors

5ht1a

post synaptic and autoreceptor

Gi mechanism

• reduce cAMP by inhibiting adenylyl cyclase

• increase opening of K+ channels hyperpolarization

• 5ht 1a receptor

5ht 2a receptors (Gq)

• affects phospholipase C which activates PKC

• highly expressed in cortex in striatum and in nucleus accumbens

• activate the phosphoinotiside in second messenger system (PLC)

LSD

hallucinogen

• psilocybin (acid)

• due to stimulation of 5ht2A receptors

ketanserin

antagonist that reduces the effects of acid and LSD reducing hallucinogenic effects

5ht and schizo

treatment of schizo is via 5ht receptor antagonist

• atypical or 2nd generation

5ht2a receptor anatagonists

clozapine (clozaril)

risperiodone (risperdal)

• antagonize 5ht2a receptors and D1 and D2 family of receptors

• have more pronounced 5ht antagonism than DA antagnism

• used to treat schizo with fewer EPS movement disorders

migraine and 5ht release

abnormal dilation of brain vessels causes migraine headaches

triptans

5ht 1b/1d agonist which causes constriction of blood vessed to reduce migraines

• sumatriptan (imitrex)

• zolmitriptan (zomig)

may also reduce central 5 ht release by stimulating terminal 5 ht autoreceptors

5ht and aggression

tph2 ko

• brain aeas involved in aggression receive substatial serotonergic innervation and express several 5ht receptor subtypes

IED

intermittent explosive disorder

• premature stop codon in 5ht 2b

• increased impulsivitiy and novelty seeking in 5ht 2b ko mice

sidis

sudden infant death

• to test this they mutated mice with a lmx1b ko which is a TF for 5HT

• significant problems with thermoregulation could not maintain body temp in cold conditions

• frequent long lasting episodes of apnea in very young mice

• these mice no longer have serotonergic cells

doi

2a and 2b agonist which rescues mutant phenotype

5ht and anxiety

ssri’s are the most common treatment for several anxiety disorders.

efficacy can be prevented by trp depletion

tested with 5ht 1a ko mice

buspar (buspirone)

to treat anxiety by increasing 1A activity

defiency in 5ht1a receptor

loss of this during critical development period may give rise to early onset anxiety issues

5ht1b or 5ht2c receptor

agonist reduce food intake and promote weight loss in rodent models of obesity

• appetite circuit within the arcute and paraventricular nuclei of hypothalamus is shown

5 ht released from drn to mrn

projections to the arcute nucleus exerts an anorexigenic effect by dual mechanisms

• stimulation of pomc neurons through 5ht2c receptors

• suppression of the npy/agrp neurons through 5ht 1b receptors

blocking 5ht by inhibiting tph2

increased marble diggining

serotonin hypothesis of depression

idea that depression is due to low levels of serotonin but this is not always true

evidence for serotonin hypothesis for depression

low 5hiaa levels found in brains of sucide victims

trp depletion of unmedicated patients in remission causes a relapse in depression symptoms

• depressed mood in healthy subjects who have a family history of depression

increased density of postsynaptic 5ht2 receptors with people with umedicated mood disorders

antidepressants and 5ht acute

antidepressant increase 5ht by blocking reuptake by ssris or tca or inhibiting maois

antidepressants and 5ht chronic

downstream changes include hippocampal neurogenesis and functional remodeling of corticolimbic circuits

stress and antidepressant treatment on bdnf

chronic antidepressant treatment not only alters monoamine transmission but also bdnf.

• protects neuron from further damage and may help repair those damaged