Neurotransmitters

Neurotransmitter Criteria

1. The chemical must be produced or found in a neuron.

2. When the neuron is stimulated, it must release the chemical.

3. When the chemical is released, it must act on a postsynaptic receptor and cause a biological effect.

4. After a chemical is released, it must be inactivated.

5. If the chemical is applied to a membrane, it must have the same effect as when it is released by the neuron.

Classes of Neurotransmitters

• Small molecule neurotransmitters – account for most of the regular synaptic activity in PNS and CNS

– e.g., acetylcholine, amines and amino acids

*act in milliseconds and generally act by binding to a specific receptor, which determines its precise postsynaptic effect.

• Neuropeptides – generally have a secondary role in neurotransmission

Larger chain of amino acids; Hypothalamus and pituitary are major contributors

– e.g., enkephalins and endorphins, releasing factors

*may act over long periods, and influence postsynaptic cell metabolism, gene expression, etc.

• Gases

– e.g., nitric oxide and carbon monoxide

*neurotransmitter that is small but appears to have long-lasting effects

Metabolism of Neurotransmitters

1. Synthesis

2. Storage

3. Release

4. Receptor binding

5. Removal

1. Synthesis

May be stimulated or inhibited by hormones, drugs

May take place in cell body (synthesis) or in axon terminals (final assembly)

Synthesis of Small molecule

1. Precursors and enzymes transported to terminal

2. Requires specific enzymes, e.g., choline acetyl transferase (CAT) for acetylcholine

Assembled towards synaptic terminals (small and easy to make)

Synthesis of Neuropeptides

– Precursors made in cell body

– Neurotransmitter synthesized in cell body or as it is transported to nerve terminal (in a vesicle)

Synthesis of Gases

NO and CO

Synthesized in axon terminals (gases diffuse so can’t make it at the cell body)

2. Storage/Packaging into vesicles

• Small molecule neurotransmitters and Neuropeptides – Stored in vesicles at nerve terminals

• Gases – Cannot be stored in cells (not synthesize in cell body; only made when needed)

3. Neurotransmitter Release

a) Small molecule neurotransmitters – Released by single impulse (action potential)

b) Neuropeptides – Released by multiple impulses

Small amount released relative to stores (can be exhausted depending on amount of stimulation)

Enough stored for 10,000 synaptic transmissions

4. Receptor Binding

• Released neurotransmitter interacts with receptor on postsynaptic terminal

• Inhibitory or excitatory effect (depends on type of post-synaptic cell receptor, not neurotransmitter)

• Rapid and point-to-point, or slow and diffuse

– Amines

– Amino acids

– Neuropeptides

Ion channels (voltage/ligand gated) are quick, direct depolarization or hyperpolarization

Second messenger system are a chain of reactions (indirect and slow) i.e. cyclic AMP

Typical Effects of Major Transmitters

Fast excitatory: sodium into cell (depolarization)

• PNS: acetylcholine (nicotinic receptor)

• CNS: glutamate (and aspartate)

Fast inhibitory: chloride/ potassium(hyperpolarization)

• GABA (mostly in brain)

• Glycine (mostly in the spinal cord)

Second-messenger effects (slow): acetylcholine (muscarinic receptor)

5. Removal and/or Inactivation

• Reuptake mechanism by presynaptic terminal

• Uptake by nearby glial cell

• Enzymatic inactivation (enzyme degrades neurotransmitter)

• Uptake by postsynaptic terminal (different than binding to receptor [activation], will have no effect and just remove from system)

• Diffuse out of synaptic cleft

Acetylcholine

• Neurotransmitter in somatic (skeletal), autonomic (sympathetic and parasympathetic) and central nervous systems

• Binds to Cholinergic receptors

Clinical Example of Acetylcholine- Alzheimer

• Decrease in cognitive capacity with aging

• Associated with decrease in choline acetyltransferase in the cortex and hippocampus

Neuron death → neurotransmitters no longer being made → atrophy and neuro-degeneration

Acetylcholine- Synthesis

• Synthesis - choline + acetyl CoA

– Catalyzed by choline acetyltransferase (CAT) enzyme

– Concentration of Ach dictates the rate of synthesis

Acetylcholine- Receptor binding

– Nicotinic receptors

• act on ion channel (FAST)

• mediate fast EPSPs

• e.g., excitatory at neuromuscular junction

– Muscarinic receptors

• use 2nd messenger (SLOW)

• postganglionic parasympathetic synapses

• e.g., inhibitory at heart

Acetylcholine- Removal

Inactivated by acetylcholinesterase (ACE) = choline + acetate

Choline is recycled back to make acetylcholine

Acetylcholine- Enhancement

Acetylcholinesterase inhibitors

Inhibit breakdown → keep acetylcholine in synaptic cleft longer

Clinical Example of Acetylcholine - Cholinergic antagonists

Blocks binding of acetylcholine

Atropine

• Competitively binds to muscarinic receptors (SLOW)

1. Mydriatic » Blocks contraction of pupillary sphincter muscle (→ dilate)

2. Cycloplegic » Paralyzes the ciliary muscles of iris (→ trouble focusing)

Tropicamide

• Shorter acting

• Mydriatic → dilates

Clinical Example of Acetylcholine - Botulinum

Interferes with release of neurotransmitter (ACh) → paralysis

Clinical Example of Acetylcholine - Myasthenia Gravis

Makes antibodies against receptors → reduces biding of ACh

Autoimmune condition

Gradual → blocks receptors then slowly destroys

Clinical Example of Acetylcholine - Curare

– Active ingredient in plant extracts (poison arrow tips)

– Binds to nicotinic receptors, prevents them from opening

– Results in weakness or paralysis by blocking neuromuscular transmission

Amines

• Catecholamines

– Dopamine

– Norepinephrine

– Epinephrine

• Serotonin

• Histamine

Amines - Receptor binding

Biogenic amines receptors use 2nd messenger system (slow)

Dopamine

Controls movement, emotional response, pleasure/pain

Feel good reward chemical in the brain

Balance and controlled movements

loss results in Parkinson’s

Dopamine- Synthesis

Tyrosine (precursor) → Dopamine (has an intermediate : dopa)

Does not cross blood brain barrier

Dopamine- Receptor binding

Inhibitory, used by substantia nigra of midbrain

Uses 2nd messenger system

Dopamine- Removal

Inactivated via reuptake mechanism

Clinical Example of Dopamine – Parkinson’s

Lack of dopamine produced by substantia nigra

Synthesis is affected

Tx: Levo-dopa = dopamine precursor which can cross blood brain barrier

– Metabolized into dopamine

Clinical Example of Dopamine – Cocaine, opium, heroin, nicotine and alcohol

Feel good drugs

Prevents reuptake

Increases the level of dopamine

Clinical Example of Dopamine – Amphetamines

Increase dopamine concentration

Pushes out of synaptic vesicles in presynaptic terminal

Increases synthesis and release

Clinical Example of Dopamine – Schizophrenia

Abnormally high levels dopamine

Dopamine receptor blockers are used to tx schizophrenics

Over production → over excites post synaptic cells

Serotonin

5-hydroxyl tryptamine (5HT)

Spinothalamic and trigeminal pathways - pain and temp control of head and body

Regulates appetite, emotion, mood, sleep, memory, learning, behavior, muscle contraction, cardiovascular and endocrine system

Clinical Example of Low Serotonin

– depression and anger problems

– obsessive compulsive

– suicide

– big appetite for carbs

– sleeping issues linked to migraines

– irritable bowel syndrome

– fibromyalgia

low-protein diet for a day → tryptophan-free amino acid mixture.

– increase in aggressive behavior and changes in sleep cycle

Serotonin- Synthesis

Synthesized from Tryptophan

Tryptophan not made in body; must be absorbed from diet

Serotonin- Receptor Binding

Inhibitory in pain pathways

Uses 2nd messenger system

Serotonin- Removal

Inactivated via reuptake mechanism

Tricyclic antidepressants inhibit re-uptake

• E.g., prozac, zoloft, paxil, SSRI

Norepinephrine

Helps form memories

Brings the nervous system to high alert

Increases heart rate and blood pressure

Norepinephrine - Synthesis

Synthesized inside nerve axon

Dopamine transported into vesicles and then converted to norepinephrine

Norepinephrine - Receptor binding

Excitatory or inhibitory (many different receptors)

2nd messenger system

Clinical Example of Norepinephrine - Amphetamines

– Releases norepinephrine and neurotransmitters dopamine and serotonin

– Induces euphoria

– Mechanism of action: increase NT release → Greater concentration in synaptic cleft

• Recreational use of amphetamine = Speed

– Performance enhancer

– Avoided in pts with glaucoma –> can cause mydriasis (affect aqueous flow) which can increase IOP

Histamine

Pacemaker function of the brain, modulates sleep

• Inhibition of histamine causes inability to maintain vigilance

Excitatory, localized in hypothalamus

Histamine: Synthesis

decarboxylation of histidine

Amino Acids - Glutamate

• Common in sensory pathways (e.g., retinal photoreceptors)

• Principal excitatory neurotransmitter in CNS

• Can be excitotoxic

• Excessive activation of glutamate receptors –> Epilepsy, excitotoxic neurodegeneration, paralysis

• Glutamate excitotoxicity in glaucoma? → retinal ganglion cells and excess of glutamate

Glutamate (AA) - Synthesis

From glutamine

Glutamate (AA) - Receptor Binding

Metabotropic and ionotropic glutamate receptors

NMDA receptor

Glutamate (AA) - Removal

Uptake by glial cell and converted into glutamine or reabsorbed by presynaptic terminal

GABA

Gamma-aminobutyric acid (GABA)

Principal inhibitory neurotransmitter in CNS

Slows the stimulating neurotransmitters that lead to anxiety

GABA- Synthesis

Produced by decarboxylation of glutamate

GABA- Receptor binding

Two types

GABA A – affects ion channels (FAST)

GABA B – utilizes 2nd messenger system (SLOW)

GABA- Removal

Active transport into astrocytes (glial cells)

Clinical Example of GABA- Benzodiazapine tranquilizers (Valium)

Increase frequency of GABA-gated chloride channel opening (hyperpolarization → inhibitory)

Inhibits post-synaptic cell receptors

Clinical Example of GABA- Barbiturates and alcohol

Potentiate chloride influx → allows for more chlorine to enter cell → prolong hyperpolarization

Inhibits post-synaptic cell receptors

Amino acids - Aspartate

Excitatory

CNS

Reabsorbed by presynaptic terminal

Amino acids - Glycine

Inhibitory (e.g., amacrine cells)

CNS

Reabsorbed by presynaptic terminal

Clinical Examples of Glycine (AA) - Strychnine

White, odorless powder

Blocks glycine-gated channels (inhibits the inhibitor)

Causes convulsions and other signs of hyperexcitability (over excitation of muscles)

Mechanism: post-synaptic cell receptors

Clinical Examples of Glycine (AA) - Hyperekplexia

excessive jumping/”startle disease”

Mutation in glycine-gated channels

Born with increased muscle tone, decrease to normal in 1 to 2 years

Exaggerated version of startle reflex to unexpected stimuli (esp. loud sounds)

Forceful blinking, grimacing, flexion of arms, contraction of leg muscles – can result in a fall

Mechanism: post-synaptic cell receptors

Peptides

AKA neuropeptides

Short chain of amino acids

Energy consuming to make and transport

Usually available in low concentrations

Synthesis from larger precursor proteins

Location: hypothalamus

Peptides - Substance P

11 amino acids

Originally isolated from gut

Localized in CNS and PNS neurons

Modulator of pain perception in spinal cord

Peptides - Enkephalins and Endorphins

Met- or leu- enkephalin, 5 amino acids

Beta-endorphin, 31 amino acids

Endogenous ligands for opiate receptors (natural pain killers)

Prominent role in pain-control circuitry

Peptides - Releasing factors and hormones

many found in cerebrum in addition to hypothalamus

all have activity in body

often co-localized with small neurotransmitter in same terminal

role may be long-term, metabolic, etc.

Peptides - Removal

Receptor desensitization and removal of the peptide by diffusion and degradation

No evidence for uptake of peptides into presynaptic terminals

Gases - Nitric oxide and carbon monoxide

Released by slow diffusion from presynaptic terminals

Enters postsynaptic neuron and has long-term effects

Found in memory and behavioral pathways

No storage, does not follow classic rules of neurotransmitter