PSYC 462: Serotonin

location of serotonergic neruons

midline of brainstem, raphe nuclei

serotonin anatomy

• widespread innervation

• dorsal and medial raphe nuclei

serotonergic neuron innervation is…

• more widespread than DA

• similar to NE

what type of molecule is 5-HT?

an indolamine, a type of monoamine

stages of 5-HT synthesis

1. tryptophan is converted to 5-HTP using tryptophan hydroxylase

2. 5-HTP is converted to 5-HT using AADC

aromatic amino acid decarboxylase (AADC) function

converts 5-HTP to 5-HT

tryptophan hydroxylase function

converts tryptophan to 5-HTP

parachlorophenylalanine (PCPA) function

• irreversibly inhibits tryptophan hydroxylase, reducing 5-HT synthesis

• the brain must synthesize new tryptophan hydroxylase to restore 5-HT levels

how to increase 5-HT synthesis?

• provide large doses of tryptophan or 5-HTP

  • 5-HTP is more effective - bypasses rate-limiting step

rate-limiting step of 5-HT synthesis

converting tryptophan to 5-HTP using tryptophan hydroxylase

tryptophan hydroxylase is found in…

serotonergic neurons only

• is used as a marker to determine which neurons are serotonergic

tryptophan transport

competes with other large neutral amino acids for BBB transport

tryptophan depletion - cocktail

• to reduce 5-HT temporarily, we can provide an amino acid cocktail

• this lowers brain tryptophan because it competes with other amino acids at the BBB, ratio is smaller

effects of tryptophan depletion cocktail - previously-depressed patients

reappearance of depression symptoms

effects of tryptophan depletion cocktail - non-depressed individuals

no depression symptoms, but increased impulsivity

what is 5-HT transported into vesicles by?

VMAT2

reserpine function

blocks VMAT2 from packaging 5-HT into vesicles, preventing monoamine storage

somatotdendritic autoreceptors - characteristics

• slow firing rate of receptor

• are usually 5-HT1A type

presynaptic autoreceptor - characteristics

inhibit release of NT at the next AP

how is serotonin reuptaken?

via SERT

what molecule degrades/breaks down 5-HT

MAO

what does 5-HT degradation yield (waste product)

5-HIAA

MAO inhibitor function

prevent breakdown of 5-HT

drugs that enhance 5-HT release

• fenfluramine

• MDMA/ecstacy

MDMA/ecstacy function

• high affinity for SERT

• disproportionate 5-HT release

• alters sensory perception, some therapeutic use for PTSD

reuptake inhibitors function/examples

• SSRIs, eg: fluoxetine (Prozac)

  • these block SERT to increase 5-HT levels

fenfluramine function

appetite suppressant with cardiac side effects - removed from market

how many 5-HT receptor families?

5-HT1 to 5-HT7

how many subtypes does 5-HT1 have

5

how many subtypes does 5-HT2 have

3

are drugs selective or nonselective for 5-HT receptors?

most are nonselective

location of postsynaptic 5-HT1A receptors

• hippocampus

• septum

• amygdala

location of somatodendritic 5-HT1A autoreceptors

cell bodies/raphe nuclei

mechanism of 5-HT1A receptors

decrease cAMP and/or open K+ channels - resulting in hyperpolarization

full agonist for 5-HT1A receptors

8-OH-DPAT

partial agonist for 5-HT1A receptors

buspirone (anti-anxiety)

5-HT1A receptor antagonist

WAY-100635

systemic 5-HT1A agonists affect…

postsynaptic receptors AND autoreceptors

• reduce overall 5-HT release

location/type of 5-HT1B/1D receptors

• presynaptic autoreceptors

• also postsynaptic, but only in striatum and NAcc

location/type of 5-HT2A receptors

• cortex

• striatum

• NAcc

• primarily postsynaptic

5-HT2A receptor mechanism

• phosphoinositide system

• increased Ca2+ → activated protein kinase C

overactivation of 5-HT2A receptor results in…

perceptual distortion

list of 5-HT2A agonists

• DOI

• LSD

DOI and LSD functions

• 5-HT2A receptor agonist

• both hallucinogenic

list of 5-HT2A receptor antagonists

ketanserin

ketanserin effect

blocks hallucinations by blocking 5-HT2A receptors (antagonist)

research methods using 5-HT

• measuring 5-HIAA in CSF

• SSRIs/receptor drugs

• genetic polymorphisms, eg: variances in SERT

• lesions of 5-HT with neurotoxins

• KO mice lacking 5-HT receptors or deleting enzymes that produce 5-HT

• psychopharmacology studies

hypophagia is caused by…

• SSRIs

• 5-HT1B receptor agonists

• 5-HT2C receptor agonists

characteristics of hypophagia

• reduce meal size, not number of meals

• animals get full faster

• food preference shifts away from fatty fods

neural mechanism of hypophagia

• disinhibition of neurons in paraventricular hypothalamus

• promotes satiety signalling

hyperphagia is caused by…

5-HT1A agonists

• activate somatodendritic autoreceptors

• reduce 5-HT neuron firing

• reduce overall 5-HT release

elevated plus maze - concept

• more time in open arms = less anxiety

• more time in closed arms = more anxiety

5-HT1A agonists - elevated plus maze

more time in open arms and less anxiety

5-HT1A knockout mice - elevated plus maze

less time in open arms, more anxiety

systemic HT1A agonists…

activate both postsnyaptic 5-HT1A receptors and somatodendritic autoreceptors

when stimulated optogenetically, BNST… (arm time)

• increasing 5-HT release = reduced anxiety and more open arm time

• decreasing 5-HT release = increases anxiety and less open arm time

  • conclusion: BNST activation reduces anxiety

which serotonin receptors increase anxiety behaviours?

5-HT2A and 5-HT2C

5-HT depletion in animals - results

attack one another more frequently

tryptophan depletion in humans - results

increased aggression in lab tasks, more likely to attack opponent in a game

low 5-HIAA in CSF is associated with…

impulsive aggression

agonists for what receptor reduce aggression?

5-HT1A and 5-HT1B

overexpression of 5-HT1A receptor is involved in…

lower 5-HT and increased aggression

what receptor agonist decrease impulsivity?

5-HT2C

what receptor ANTAGONIST increase impulsivity?

5-HT2C