NEURO Chapter 6: Neurotransmitter Systems

3 requirements to be a NT

1) production and storage in presynaptic neuron

2) release upon stimulation

3) experimental results yield same effect as presynaptic release

Dale’s principle, is it correct?

only a single NT is released by a neuron - wrong

Diffuse modulatory systems

small number of neurons that manufacture and release NT, connected to rest of brain through axons

Cholinergic neurons: diffuse modulatory systems

• basal forebrain complex

  • medial septum —> hippocampus: memory formation, spatial

  • basal nucleus of Meynert —> rest: arousal, mood

• pontomesencephalotegmental complex —> dorsal thalamus: sensory relay

Cholinergic neurons: production

Acetyl-CoA + choline —> Acetylcholine (use choline acetyltransferase ChAT)

• in membrane —> gets packed up into vesicles by ACh transporter

• choline: rate-limiting factor, can be increased through diet

Cholinergic neurons: deactivation

free-floating acetylcholinesterase (AChE) break down ACh to acetic acid and choline

• choline reuptake through choline transporter (activated by Na+ gradient)

• AChE produced in glial cells

Catecholaminergenic neurons

1) Dopaminergic (Dopamine)

2) Noradrenergic (Norepinephrine)

3) Adrenergic (Epinephrine)

Dopaminergic neurons: diffuse modulatory systems

Susbtantia Nigra —> basal ganglia: voluntary movement

• ex) Parkinson’s disease

Ventral tegmental area —> frontal lobe: reward pathways, desire

• rat experiment

Dopaminergic neurons: production

Tyrosine —> l-dopa (Tyrosine Hydroxylase) —> Dopamine (dopa decarboxylase)

• TH: rate limiting factor 1) higher AP and Ca2+ concentration in cell stimulate production of TH 2) decreased catecholamine release increase cellular concentration of catecholamines —> less TH produced

What is used to treat Parkinsons? Why is it ineffective in the long term?

l-dopa, which creates an abundance of dopamine in the basal ganglia, but overtime this abundance causes the brain to downregulate production of dopamine

Dopaminergic neurons: reuptake

DAT in presynaptic neurons and astrocytes take dopamine —> Monoamine Oxide (MAO) breakdown dopamine in mitochondria and liver

• MAO inhibitors are antidepressants

explain mechanism of cocaine

Blocks DAT —> dopamine stays in synaptic cleft for longer

explain mechanism of amphetamines

1) enters presynaptic neuron through DAT

2) reverses VMAT → dopamine flows out of vesicle into the cytoplasm

3) reverses DAT → cytoplasmic dopamine flows out to the synaptic cleft

→ increased release of dopamine

Noradrenergic neurons: diffuse modulatory system

Locus coeruleus (LC) → rest of the brain

• 1 neuron → 250,000 neurons

• mood, awakeness, sleep cycle, arousal

• stress response, response to new stimuli

Noradrenergic: production

Dopamine → norepinephrine (DBH)

• created in vesicles

Adrenergic

Norepinephrine → epinephrine (PNMT)

• synthesized in cytosol

Serotonergic neurons: diffuse modulatory system

Raphe nuclei

→ caudal: pain

→ rostral: mood, sleep/wake cycle

Serotonergic neurons: production

Tryptophan → 5-HTP (tryptophan hydroxylase) → 5-HT

• rate limiting factor: tryptophan - in food

Serotonergic neurons: deactivation

reuptake through SERT (plasma membrane serotonergic transporters)

• reused

• target of SSRI (selective serotonin reuptake inhibitors)

Serotonin (5-HT) regulation

through 5-HT 1d receptors in presynaptic neuron that downregulates the production of 5-HT when 5-HT binds to it

Why do SSRIs take a while to work?

due to the regulation by 5-HT 1d receptors. It takes a while for the abundance of serotonin to cause desensitization of 5-HT 1d receptors

Amino Acidergic Neurons: production

Glutamine → Glutamate (Glutaminase) → GABA (GAD)

• GAD only expressed in GABAergic neurons → can be used as a marker

• packaging by vGlut and vGAT

Glutamate

primary excitatory NT

GABA

primary inhibitory NT

Amino acidergic neurons: deactivation

reuptake to presynaptic cells or astrocytes

• Glutamate: EAAT

• GABA: GAT

→ converted to glutamine and recycled in neurons

Endocannabinoids

retrograde messengers: high concentration of NT in synaptic cleft → high concentration of Ca2+ in postsynaptic cell → activation of enzyme that makes endocannabinoids → travel to cannabinoid receptor in presynaptic neuron → triggers downregulation of NT synthesis or release

• manufactured on demand

• membrane permeable

Nitric Oxide

• vasodilation

• long term potentiation: learning and memory

• regulate Glu/GABA activity

• retrograde messenger