W4L2: Peptides, Lipids, Nucleosides & Gases

What prevents peptides, nucleosides, lipids & gases from being classified as ‘true’ neurotransmitters?

They do not satisfy all of the following criteria:

• Present in presynaptic terminals

• Released from presynaptic terminals after neuron fires

• Existence of receptors on postynaptic neurons

What is a peptide?

2 or more amino acids which are the result of protein hydrolysis

• Act similarly to neurotransmitters in that they can transport compounds between membranes, lowering the potential of neurons firing

Where does peptide ‘synthesis’ & release occur?

• Most peptides are not ‘synthesised’ but are the products of protein hydrolysis w/n the terminal button

• Proteins/peptides transported down the axon & modified in the terminals

• Commonly released alongside other neurotransmitters/neuromodulators to wither ^ or v its effectiveness

What is the best-known family of peptide neurotransmitters?

Endogenous opioids; originate internally & act on opioid receptors (mostly pain receptors)

What is the difference between endogenous opioids & opiates?

• Endogenous opioids: originate internally

• Opiates: drugs (e.g. morphine, heroin & opium)

What are opiates best known for?

Their analgesic (pain relief) & euphoric properties (especially in heroin)

How does historical use of opium show how pharmacokinetics influences the addictiveness of drugs?

• England: pain relief liquid

• China: smoked through pipes

  • Shows how addictive drugs can be depending on their method of consumption;

    • Smoking → 'euphoria'

    • Orally → slower effects

What is heroin?

A highly addictive full endogenous opioid agonist (fully activates opioid mu receptors) which is not particularly neurotoxic, but causes death by respiratory failure.

What is buprenorphine & what is it used for?

• Partial opioid agonist

• Similar downstream effects to heroin (small degree of stimulation), used as maintenance treatment for heroin (b/c it is a partial agonist → only stimulates it to a small degree)

  • Not as addictive → doesn't produce the same 'high'

  • Very strong affinity to the receptor → prevents people w/ heroin addiction from feeling 'high', even if they do take heroin subsequent to buprenorphine (b/c it is being dominated by the buprenorphine

What is naloxone & what is it used for?

• Full opioid antagonist

• Used commonly as an emergency medicine → blocks action of the µ receptor completely

  • Suppresses the NS

  • Can't be as a long-term treatment b/c it is a full antagonist--> immediate withdrawal symptoms

What is methadone & what is it used for?

• Full opioid agonist

• Very similar to heroin → used in heroin maintenance treatment

• Nowhere near as addictive b/c the effects are very slow i.e. don't get the 'high' that comes w/ heroin use

What are lipids?

• Naturally occurring molecules that include fats, waxes, etc.

• Hydrophobic / lipophilic

• Main biological function = energy storage, signalling, + providing structural components of cell membrane

How are lipid neurotransmitters/neuromodulators produced

It is still unclear

What are endocannabinoids & what do they act on

• Endocannabinoids: best known lipid neurotransmitters in the brain

• Act on CB1 & CB2 receptors

  • CB1: responsible for psychological effects

  • CB2: found in the peripheral tissue

What is the effect of CB1 receptor activation?

• Shortens the duration of APs in the presynaptic neuron → v neurotransmitter release

• Regulation of presynaptic neurons + release of neuromodulators; receptors modulate the modulators

What is THC?

The active ingredient in cannabis/marijuana that acts on CB1 receptors, primarily in the hippocampus, to prevent the release of neurotransmitters & hence lowering memory functioning

• Therapeutically used to reduce nausea, relieve asthma attacks, & relieve glaucoma

Provide some examples of how different effects are produced when CB1 receptors are activated in different areas of the brain

Describe the timeline of medicinal cannabis use in Australia

• 2016: Access to Medicinal Cannabis Act passed in Victoria

• 2017: Children w/ severe intractable Epilepsy were the first group to access cannabis

• Current (VIC): any medical practitioner can prescribe medicinal cannabis if they believe it is clinically appropriate to do so

  • MPs do not need to gain accreditation or be specialists in a particular field

  • Medicinal cannabis being considered as treatment for epilepsy, pain, & multiple sclerosis

What are nucleosides & how are they obtained?

A subunit of nucleic acids, including the nitrogenous base + pentose sugar

• Usually obtained by hydrolysis of nucleic acids

• Often ‘co-transmitters’; modulate the release of other transmitters

What is adenosine?

A nucleoside that forms from the breakdown of ATP, the primary energy source in cells for transport & enzymes

How do adenosine levels fluctuate throughout the day?

Adenosine levels gradually rise throughout the day when ATP is used, promoting sleep & suppressing arousal in normal conditions

• Stimulates cells which suppress the NS

What happens at synapses where adenosine is the primary neurotransmitter?

High post-synaptic firing → sleepiness

What is caffeine & how does it work?

Adenosine receptor antagonist which blocks the natural action of adenosine

• Adenosine ^ firing rate in brain areas which promote sleepiness so caffeine ^ alertness by v the firing/activation of these neurons

• ‘Caffeine crash’ when the effect wears off b/c all of the adenosine is still in the synaptic cleft

What is a gas?

An air-like fluid substance which expands freely to fill any space available, irrespective of its quantity

What are the 2 gases that neurons use as neurotransmitter?

• Nitric oxide (NO)

• Carbon monoxide (CO)

What is nitric oxide?

A gas involved in vasodilation by increasing the size of blood vessels to increase blood to areas that are highly metabolically active

• NOT nitrous oxide (NO2) = laughing gas/nangs

What & where is nitric oxide produced from in the brain?

• Produced from Arginine (amino acid)

• Produced in subpopulation of 1-2% of neurons in the cortex

What is the function of nitric oxide in the brain?

Unclear

• Involved in learning & memory through effects on synaptic plasticity

• Dilates blood vessels in regions of the brain that become metabolically active

How is nitric oxide different to other neurotransmitters?

• NOT synthesised & stored in vesicles

• Produced throughout the cell (incl. dendrites) & diffuses out of the cell as soon as it is produced

• Does NOT activate receptors i.e. simply enters the neighbouring cell

• Very short lived & is degraded/reacted w/n a few seconds of being produced

What is the site of action of nitric oxide?

• Can act on several nearby neurons, even those not connected by a synapse, BUT

• Short half-life of NO → it’s action will be restricted to a limited area, w/o the necessity for enzymatic breakdown or cellular reuptake