Neurotransmitters and Neuromodulators

What 3 elements does the synapse consist of?

1. Presynaptic membrane - formed by the terminal button of an axon

2. Postsynaptic membrane - composed of a segment of dendrite or cell body

3. Synaptic cleft - space between presynaptic and postsynaptic membrane

What are neurotransmitters (NT)?

• Endogenous chemical

• Transmits signals across a synapse from one neurone to another target neurone, muscle cell or effector cell

• Cause rapid excitatory or inhibitory effects.

What are neuromodulators (NM)?

• Endogenous chemical

• Released from one neurone but affects groups of neurones or effector cells that have the appropriate receptor

• May not be released at synaptic sites

• Often acts through second messengers

• Effects are slower and longer-lasting

List the main neurotransmitters and neuromodulator classes

• Acetylcholine (NT)

• Monoamines (NT; NM): Catecholamines (dopamine, norepinephrine, epinephrine), Indolamines (serotonin)

• Amino acids (NT; NM): Glutamate, GABA, Glycine

• Peptides (NT; NM): Endorphins, Enkephalins

• Lipid substances (NT): Anandamide, Leptin

• Nucleosides (NM): Adenosine

• Soluble gases: Nitric Oxide, Carbon Monoxide

NT and NM classes

Acetylcholine - NM or NT?

NT

NT and NM classes

Monamines - NM or NT? Examples?

NT and NM

• Catecholamines - dopamine, norepinephrine, epinephrine

• Indolamines - serotonin

NT and NM classes

Amino acids - NM or NT? Examples?

NT and NM

• Glutamate

• GABA

• Glycine

NT and NM classes

Peptides - NM or NT? Examples?

NM and NT

• Endorphins

• Enkephalins

NT and NM classes

Lipid substances - NM or NT? Examples?

NT

• Anandamide

• Leptin

NT and NM classes

Nucleosides - NM or NT? Examples?

NM

• Adenosine

NT and NM classes

Soluble gases - NM or NT? Examples?

NM

• Nitric oxide

• Carbon monoxide

What are the major ‘slow’ neurotransmitters?

• Acetylcholine

What are the main roles of acetylcholine in the human brain and body?

• Peripheral nervous system – contraction of skeletal muscles

• Autonomic nervous system

• Brain – control of plasticity, arousal and reward

How is acetylcholine synthesised and stored?

• Synthesised in presynaptic terminals from choline and acetyl-CoA

• Stored in small synaptic vesicles

How is acetylcholine released into the synaptic cleft?

• Action potential arrives ant presynaptic neurone

• Presynaptic plasma membrane depolarises

• ACh is released by vesicular exocytosis

How is acetylcholine removed from the synaptic cleft?

• Rapidly removed by acetylcholinesterase (AChE)

• Choline is taken up by specific transporters

What types of receptors does acetylcholine act on?

• Nicotinic receptors

• Muscarinic receptors

What drugs stimulate and block nicotinic and muscarinic receptors?

Nicotinic receptors: stimulated by nicotine, blocked by curare

Muscarinic receptors: stimulated by muscarine, blocked by atropine

Nicotinic ACh Receptors

What type of receptors are nicotinic ACh receptors?

Ligand-gated ion channels

Nicotinic ACh Receptors

What happens when ACh binds to nicotinic receptors?

• Opening of the central ion pore

• Allowing Na⁺ influx

• Causing depolarisation and excitation of the postsynaptic cell

• Action potential generated

Muscarinic ACh Receptors

What type of receptors are muscarinic ACh receptors?

• G protein–coupled receptors

• Classified into five groups - M1 - M5

Muscarinic ACh Receptors

Which muscarinic receptors activate Gq/11 proteins and what is the effect?

M1, M3 and M5 receptors activate Gq/11:

• When Ach binds to the receptor, the α subunit of the Gq/11 protein separates from the βγ subunits

• The α subunit binds and activates Phospholipase C (PLC)

• PLC produces 2 second messengers: diacylglycerol (DAG) and inositol-3 phosphate (IP3)

• This triggers Ca²⁺ release from the intracellular stores

• Produces a slow depolarising EPSP

• Leads to overall excitation of the postsynaptic neurone

Muscarinic ACh Receptors

Which muscarinic receptors activate Gi/o proteins and what is the effect?

M2 and M4 receptors activate Gi/o:

• When Ach binds to the receptor, the the α subunit of the Gi/o protein separates from the βγ subunits

• The α subunit binds and inhibits adenylyl cyclase

• Inhibit voltage-gated Ca²⁺ channels

• Leads to overall inhibition of the postsynaptic neurone

What is the main source of acetylcholine in the brain?

The Nucleus Basalis of Meynert in the basal forebrain

What are axons of neurones in the nucleus basalis of meynert known as?

Cholinergic fibers / neurones » release Ach

Where do cholinergic fibres from the Nucleus Basalis of Meynert project?

• Neocortex

• Hippocampus

• Amygdala

What is the role of acetylcholine in the neocortex?

• Cholinergic fibers extend to the neocortex

• Ach activates muscarinic M1 receptors here which enhances the processes that are involved in memory consolidation:

• Muscarinic M1 receptors are Gq/11-coupled receptors

• Activation by ACh leads to PLC activation → IP₃ and DAG production → Ca²⁺ release

• This causes slow depolarising EPSPs and increased neuronal excitability

• Increased excitability supports synaptic plasticity, which is essential for memory consolidation

What are the roles of acetylcholine in the hippocampus and amygdala?

Cholinergic fibers project to the hippocampus and amygdala:

• Hippocampus – regulate memory formation

• Amygdala – regulate emotions

What other brain regions contain cholinergic neurones which release ACh?

• Interneurones in the striatum

• Dorsal lateral tegmental nucleus in the midbrain

Which regions of the brain do cholinergic neurones of the dorsal lateral tegmental nucleus in the midbrain project to?

• Thalamus - regulates sensory processing

• Cerebellum - regulates movement coordination

Why do drugs acting on CNS cholinergic receptors have peripheral nervous system (PNS) effects?

Because both muscarinic and nicotinic receptors mediate activity in the autonomic nervous system

Example of a nicotinic receptor agonist

What CNS effects can nicotinic receptor agonists (e.g. nicotine) cause?

E.g. nicotine

Convulsions

Example of a muscarinic receptor agonist

What CNS effects do muscarinic receptor agonists have?

What CNS effects do muscarinic receptor agonists have?

E.g. Amanita mushrooms

CNS:

• Vertigo

• Confusion

• Weakness

• Coma at higher doses

PNS:

• Salivation

• Sweating

• Pupil contraction

• Dyspnoea

• Abdominal pain

• Diarrhoea

Example of muscarinic receptor antagonists

What CNS effects do muscarinic receptor antagonists have?

What PNS effects do muscarinic receptor antagonists have?

e.g. Atropine, Scopolamine

CNS:

• Drowsiness

• Euphoria

• Amnesia

• Fatigue

• Dreamless sleep

• Excitement

• Hallucinations

PNS:

• Pupil dilation

• Decreased salivation

• Decreased secretion in the pharynx and respiratory tract

• Increased heart rate

• Decreased gut motility and secretion

• Decreased bladder tone

What do anticholinesterase inhibitors do?

• Block ACh degradation

• Causing accumulation of ACh in synapses

Why are anticholinesterase inhibitors considered dangerous?

They are very toxic and can be used as chemical weapons

What therapeutic use do anticholinesterase inhibitors have?

Some are used as therapeutic agents in Myasthenia gravis

What are the CNS effects of anticholinesterase inhibitors?

• Slurred speech

• Confusion

• Loss of reflexes

• Convulsions

• Sometimes coma at higher doses.

What are the PNS effects of anticholinesterase inhibitors?

• Pupil constriction

• Watery nasal discharge

• Bronchiolar secretion (wheezing)

• Nausea

• Vomiting

• Cramps

• Diarrhoea

• Involuntary urination

• Sweating

• Twitching

What is dopamine?

• Neurotransmitter

• Of the catecholamine family

What are the main roles of dopamine in the human brain and body?

• Control of movement

• Emotional response

• Control of pleasure and pain

How is dopamine synthesised and stored?

• Synthesised in the presynaptic terminals of dopaminergic neurones from amino acid tyrosine

• Stored in large dense core vesicles

How is dopamine released?

Released by vesicles exocytosis

What happens when dopamine binds to its receptors?

Produces either excitatory or inhibitory postsynaptic effects depending on the type of postsynaptic receptor

How is dopamine removed from the synaptic cleft?

removed by dopamine transporters

How is dopamine degraded?

degraded by the enzyme monoamine oxidase (MAO)

What type of receptors are dopamine receptors?

G protein-coupled receptors

What are the two main families of dopamine receptors?

• D1-like dopamine receptors (D1, D5)

• D2-like dopamine receptors (D2, D3, D4)

D1-like Dopamine Receptors

What G protein do D1-like dopamine receptors activate?

Gs

D1-like Dopamine Receptors

Intracellular signalling pathway

• When dopamine binds to the D1-like receptor, the α subunit of the Gs protein separates from the βγ subunits

• The α subunit binds to and activates adenylyl cyclase

• Leads to stimulation of various voltage-gated channels

• Leads to overall excitation of the postsynaptic neurone

D1-like Dopamine Receptors

What is the overall effect of D1-like dopamine receptor activation?

• Stimulation of various voltage-gated channels

• Leading to overall excitation of the postsynaptic neurone

D2-like Dopamine Receptors

What G protein do D2-like dopamine receptors activate?

Gi/o

D2-like Dopamine Receptors

Intracellular signalling pathway

• When dopamine binds to the D2-like receptor, the the α subunit of the Gi/o protein separates from the βγ subunits

• The α subunit binds and inhibits adenylyl cyclase

• Inhibit various voltage-gated channels

• Leads to overall inhibition of the postsynaptic neurone

How is dopamine action terminated at the synapse?

• By re-uptake across the presynaptic membrane mediated by dopamine transporters

• This is an energy dependent process

How is the ion gradient required for dopamine transport generated?

Na+/K+ ATPases use energy from ATP hydrolysis to create a concentration gradient of ions across the presynaptic membrane

How does dopamine enter the presynaptic neurone during reuptake?

Co-transport of Na+ and Cl- ions and dopamine from the synaptic cleft

What is the role of potassium ions in dopamine transport?

• K+ ions bind to the transporter allowing it to return to the outward position

• Release of K+ ions into the synaptic cleft equilibrates the ionic gradient across the pre-synaptic membrane

Mesolimbic & Mesocortical Pathways

What is the main source of dopamine in the brain?

neurones located in the Ventral Tegmental Area (VTA)

Mesolimbic & Mesocortical Pathways

What is the Mesolimbic Dopamine pathway?

Neurones in the VTA which axons extend to limbic areas e.g. Nucleus Accumbens

Mesolimbic & Mesocortical Pathways

Function of dopamine released in the nucleus accumbens by the mesolimbic dopamine pathway

Regulates the mood and reward centres

Mesolimbic & Mesocortical Pathways

Effects of diseases and drugs which increase dopamine release in the mesolimbic pathway

• Positive psychotic symptoms

• Aggressive and hostile behaviours.

Mesolimbic & Mesocortical Pathways

What is the Mesocortical Dopamine pathway?

Neurones in the VTA which axons extend to the prefrontal cortex

Mesolimbic & Mesocortical Pathways

Function of dopamine released in the prefrontal cortex by the mesocortical dopamine pathway

regulates attention and memory

Nigrostriatal Pathway

What is another major source of dopamine in the brain?

Substantia Nigra in the midbrain

Nigrostriatal Pathway

Where do substantia nigra neurones project?

To the striatum of the basal ganglia region

Nigrostriatal Pathway

What is the function of the nigrostriatal dopamine pathway?

regulation of motor function

Nigrostriatal Pathway

What are the effects of dopamine deficiency in this pathway?

• Rigidity

• Akinaesia or bradykinaesia

• Tremor

• Akathisia and dystonia (symptoms of Parkinson’s disease)

Nigrostriatal Pathway

What are the effects of hyperactivity in this pathway?

• Chorea

• Dyskinesias

• Tics

Tuberoinfundibular Pathway

What is the third main source of dopamine in the brain?

Arcuate nucleus of the hypothalamus

Tuberoinfundibular Pathway

Where does dopamine released from the arcuate nucleus act?

It is released into the portal blood system and travels to the anterior pituitary

Tuberoinfundibular Pathway

What is the effect of dopamine on the anterior pituitary?

It acts on prolactin-secreting cells (lactotrophs) to suppress prolactin release

What drugs act as dopamine receptor agonists and mimetics?

DA transporter inhibitors:

• Amphetamine - causes release of dopamine

• Cocaine - prevents reuptake of dopamine

» drugs of abuse

What dopamine precursor is used therapeutically?

• L-DOPA

• Treatment for Parkinson’s disease

What are dopamine receptor antagonists used for?

anti-schizophrenic or anti-psychotic drugs (D2 antagonists)

What is noradrenaline?

AKA norepinephrine

• Neurotransmitter

• Of the catecholamine family

What are the main roles of noradrenaline in the human brain and body?

Autonomic nervous system control – sympathetic nervous system
CNS – control of alertness, rest cycles, attention and memory

How is noradrenaline synthesised and stored?

• Synthesised in the presynaptic terminals of adrenergic neurones from amino acid tyrosine

• Stored in large dense core vesicles

How is noradrenaline released?

By vesicle exocytosis

How does noradrenaline act at the synapse?

• It binds to specific adrenergic receptors

• Produces either excitatory or inhibitory postsynaptic effects depending on the postsynaptic receptor

How is noradrenaline removed and degraded?

• Removed by adrenergic transporters

• Degraded by monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT)

What type of receptors does noradrenaline bind to?

Adrenergic receptors » G protein-coupled receptors

How are adrenergic receptors classified?

α receptors: α1 and α2
β receptors: β1, β2 and β3

α1 receptors

What G protein are α1 receptors coupled to?

Gq/11

α1 receptors

Intracellular signalling pathway

• When NA binds to the α1 receptor, the α subunit of the Gq/11 protein separates from the βγ subunits

• The α subunit binds and activates Phospholipase C (PLC)

• PLC produces 2 second messengers: diacylglycerol (DAG) and inositol-3 phosphate (IP3)

• This triggers Ca²⁺ release from the intracellular stores

• Produces a slow depolarising EPSP

• Leads to overall excitation of the postsynaptic neurone

α2 Receptors

What G-protein are α2 Receptors coupled to?

Gi/o

α2 Receptors

Intracellular signalling pathway

• When NA binds to the α2 receptor, the the α subunit of the Gi/o protein separates from the βγ subunits

• The α subunit binds and inhibits adenylyl cyclase

• Leads to the inhibition of various voltage-gated channels

• Leads to overall inhibition of the postsynaptic neurone

β Receptors

What G-protein are β Receptors coupled to?

Gs

β Receptors

Intracellular signalling pathway

• When NA binds to the β receptor, the the α subunit of the Gs protein separates from the βγ subunits

• The α subunit binds to and stimulates adenylyl cyclase

• This leads to the activation of various voltage-gated channels

• Leads to overall excitation of the postsynaptic neurone

How is the activity of NA terminated at the synapse?

Same as dopamine

What is the main source of NA in the brain?

Locus Coeruleus, located in the Pons region of the Brain Stem

Where do neurones in the Locus Coeruleus nucleus project their axons to AKA where is NA released in the brain?

• Neocortex

• Limbic system

• Diencephalon

• Medulla oblongata

• Spinal cord

Function of NA in the neocortex

• Regulate attention and concentration

• Via activation of a2 receptors

Function of NA in the frontal cortex

• Regulate mood

• Via activation of B1 receptors

Function of NA in limbic areas

Regulate emotions

Function of NA in the medulla oblongata

Regulate cardiovascular centres

NA Receptor Agonists and Mimetics

NA transporter inhibitors

• e.g. Amphetamine, Cocaine

• Regulate wakefulness and alertness

MOA (moamine oxidase) inhibitors

• Impairs cognitive processes = euphoria, insomnia, hallucinations, delusions

NA Receptors Antagonists

Beta blockers

What is serotonin (5-HT)?

• Neurotransmitter

• Of the indolamine category

Role of serotonin in the human brain and body

• Controls mood, appetite, sleep

• Regulates cognitive functions e.g. memory, learning

How is serotonin synthesised?

• In presynaptic terminals of serotonergic neurones from amino acid tryptophan

• Stored in large dense core vesicles