Neurotransmitters

Question 1

Discovery of neurotransmitters

Answer 1

• Otto Loewi’s experiment showed that cells use chemical transmission
• By electrically stimulating the vagus nerve, Loewi made a dissected frog heart beat slower
• Then, Loewi took a sample of the fluid around the first heart and applied it to the second heart
• This caused the second heart to beat slower ⇒Chemical released by the vagus nerve was controlling the heart rate
• We now know this is the neurotransmitter acetylcholine
• Electrical signals (action potentials) trigger a chemical signal (release of neurotransmitter from synapses)

Question 2

What defines a neurotransmitter

Answer 2

• It’s synthesised and stored in the presynaptic neuron
• It’s released by the presynaptic axon terminal upon stimulation
• When experimentally applied, must produce a response in the postsynaptic cell that mimics the response produced by the release of neurotransmitter by the presynaptic neuron
• There must be some retrieval mechanism to remove it from the site of action

Question 3

Neurotransmitter classification

Answer 3

1. By structure e.g. biogenic amines, amino acids etc
2. By function i.e. excitatory vs inhibitory
3. By receptor (that it binds to) subtype i.e. ionotropic or metabotropic

Question 4

Neurotransmitter lifecycle

Answer 4

1. Uptake of precursors + synthesis
2. Storage
3. Release
4. Receptor interaction
5. Inactivation

Question 5

Storage of neurotransmitters

Answer 5

• Small molecule transmitter
  
  • Synthesised at terminals; packaged in small synaptic vesicles
• Peptide transmitter
  
  • Synthesised at endoplasmic reticulum and transported to the the synapse; packaged in large dense-core vesicles

Question 6

Release of neurotransmitters

Answer 6

Exocytosis = fusion of the vesicle membrane with the presynaptic membrane

Question 7

Categories of neurotransmitters

Answer 7

1. Small molecule (i.e. not proteins) e.g. acetylcholine
2. Biogenic amines
   
   1. Catecholamines e.g. dopamine, norepinephrine, epinephrine
   2. Serotonine
3. Amino acids: single molecule, building blocks of protein
   
   1. Glutamate (excitatory)
   2. GABA (inhibitory)
4. Neuropeptides - lower in concentration, in more specific places. Big molecules, small proteins
   
   1. Substance P
   2. Endorphines
   3. Enkephalins
   4. Dynorphins

Question 8

Agonist

Answer 8

A chemical that binds to and activates a receptor

Question 9

Antagonist

Answer 9

A chemical that binds to and blocks a receptor

Question 10

Ionotropic receptors

Answer 10

• Ionotropic receptors can directly “open” or “close” an ion channel
• When neurotransmitter binds to the receptor, the receptor changes conformation, creating an opening for ions to travel through.
• Fast synaptic transmission
• Local and short-term effects

Question 11

Metabotropic receptors

Answer 11

• Metabotropic receptors do not have ion channels. Neurotransmitter binds to a G protein-linked receptor and acts through an intracellular second messenger
• In some cases, the secondary messenger will bind to and open ion channels located elsewhere on the membrane
• In other cases, the secondary messenger will trigger a series of enzymatic reactions (Second-messenger cascade)
• This can alter postsynaptic metabolism and indirectly cause ion channels to open
• Indirect action
• Promotes long-lasting effects (typically 100s of ms, but sometimes several hours)

Question 12

Excitatory vs inhibitory postsynaptic potentials

Answer 12

• Resulting Postsynaptic Potentials are called excitatory (or EPSPs) if they increase the likelihood of a postsynaptic action potential occurring, and inhibitory (or IPSPs) if they decrease this likelihood.
• Whether a postsynaptic response is an EPSP or an IPSP depends on the type of channel that is coupled to the receptor.
• If Na+ influx occurs the membrane will depolarize (EPSP)
• If Cl- influx occurs the membrane will hyperpolarize (IPSP)
• Determined by receptor type on postsynaptic neuron, not neurotransmitter itself.

Question 13

Acetylcholine

Answer 13

• Small molecule neurotransmitter
• Present at many sites within the brain and body, including the neuromuscular junctions
• Two receptor types:
  
  • Nicotinic receptors (ionotropic)
  • Muscarinic receptors (metabotropic)
• Excitatory: allows sodium (Na+) to enter the cell
• Function: key role in learning and memory (implicated in Alzheimer’s disease)
  
  • Treatments are acetylcholinesterase (=enzyme that breaks down acetylcholine and removes it from the synaptic cleft) inhibitors: these increase Acetylcholine levels in the brain

Question 14

Catecholamines

Answer 14

• Dopamine, norepinephrine, epinephrine
• All synthesised through the same pathway
• Precursor: Tyrosine (essential amino acid)
• Regulation of movement, mood, attention and visceral function

Question 15

Norepinephrine (noradrenaline)

Answer 15

• Norepinephrine (noradrenaline)
• Involved in the “fight or flight response”:
• Mobilizes the brain and body for action by activating the sympathetic nervous system
• It increases heart rate, blood flow to skeletal muscle, triggers the release of glucose from energy stores
• Levels are lowest during sleep, rises during wakefulness, and reaches much higher levels during situations of stress or danger
• Increases arousal and alertness, promotes vigilance, enhances formation and retrieval of memory, and focuses attention; it also increases restlessness and anxiety.

Question 16

Dopaminergic systems

Answer 16

1. Mesolimbic pathway: ventral tegmental area (VTA) of the midbrain to the ventral striatum → reward/reinforcement learning
2. Mesocortical pathway: VTA to prefrontal cortex→ planning/short term memory
3. Nigrostriatal pathway: substantia nigra of the midbrain to the dorsal striatum → motor functions, Parkinson’s disease (degeneration of substantia nigra)

Question 17

Serotonin

Answer 17

• Precursor: Tryptophan, an essential amino acid found in grains, meat, dairy products and chocolate
• Serotonergic neurons are found in the raphe nuclei of the pons and upper brainstem, which then project widely throughout the cortex
• Serotonin has diverse functions: implicated in the modulation of mood and sleep, as well as body temperature, appetite and metabolism
• Drugs used in the treatment of depression and anxiety act specifically on serotonergic neurons, and tryptophan depletion lowers mood and causes relapse of depression in at-risk groups

Question 18

Glutamate

Answer 18

• The major neurotransmitter for excitatory neurons is glutamate, and it is estimated that over half of all brain synapses release this agent.
• Glutamate binds to NMDA receptors and AMPA receptors, which control long-term potentiation (LTP)
• LTP = synaptic connections between neurons becoming stronger with frequent activation. LTP is thought to be a way in which the brain changes in response to experience ⇒ learning and memory

Question 19

GABA

Answer 19

• Most inhibitory neurons in the brain and spinal cord use either GABA or glycine as a neurotransmitter.
• As many as one-third of the synapses in the brain use GABA as their neurotransmitter

Question 20

Neuropeptides

Answer 20

• Neuropeptides are small protein-like substances produced and released by neurons present in tissues at much lower concentrations than conventional neurotransmitters released from large dense core vesicles
• Most synapses use both conventional neurotransmitters and neuropeptides
• Main categories include: brain/gut peptides, opioid peptides, pituitary peptides and hypothalamic releasing hormones
• Longer-chain molecules, compared to conventional neurotransmitters
• Neuropeptides typically produce neuronal responses with slow onset and long duration → G-protein coupled receptor
• Can act as neuromodulators since their effects are to potentiate or depress the effects of a second transmitter

Question 21

Substance P

Answer 21

• Brain/gut peptide
• Hippocampus, amygdala, and GI tract
• Vasodilator, Involved in pain signalling, ‘First line’ defense system
• Released in response to noxious/extreme stimuli (stressors)
• E.g. to toxicants/poisons, activates the vomiting center in the medulla

Question 22

Opioid peptides

Answer 22

• Opioid peptides are widely distributed throughout the brain and are often co-localized with other small-molecule neurotransmitters such as GABA and 5-HT. Opioid peptides act at three distinct types of opioid receptors, namely, μ-, δ-, and κ-opioid receptors.
• In general, these peptides tend to be depressants: pain relief, anxiety suppression, leading to feelings of well being.
• 3 main classes: endorphins, enkephalins, dynorphins.
• Endorphins are produced by the pituitary gland in response to pain and stress
• But their release can also be triggered by exercise, spicy food, chocolate, sex
• Opioids are also involved in complex behaviors such as sexual attraction and aggressive/submissive behaviors.

Question 23

Receptor

Answer 23

Membrane protein with binding sites for a neurotransmitter

Question 24

Pharmacology of binding sites

Answer 24

Which transmitters affect them and how drugs interact with them

Question 25

Kinetics of the transmitter binding process

Answer 25

The duration of the effect

Question 26

Selectivity of the ion channel

Answer 26

Excitation or inhibition

Question 27

Conductance

Answer 27

Magnitude of the effects

Question 28

Affinity

Answer 28

Ability to bind with a particular transmitter

Question 29

Divergence

Answer 29

Each neurotransmitter has multiple receptors

Question 30

Inactivation of neurotransmitters

Answer 30

Various mechanisms for NT removal from the synaptic cleft:

• Transport
• Deactivation by enzymes e.g. acetylcholinesterase
• Diffusion