LIFE1051 Fundamentals of Neuroscience

Neurochemistry

Dr Then Sue-Mian
 Learning objectives

• Describe the basic pathways of glucose

metabolism in the brain.
• Explain why the brain has a high metabolic
demand.
• Describe the main classes of neurotransmitter
(amines, amino acids etc) and illustrate their
associated metabolic pathways.
• Outline the common drugs of abuse and their
targets.
Neurochemistry

Metabolism

Intercellular
signalling

Intracellular
signalling
Metabolism

Protein Polysaccharides Lipids

Amino acids Glucose Glycerol

Fatty acids

Pyruvate

Acetyl-CoA

NH3 CO2 + H2O + energy (ATP)

 Brain energy metabolism

• 2 % of body weight
• 20 % resting metabolic rate
• 50 - 80 % of available O2
• 10 % of available glucose
• 20 % cardiac output
• Metabolic rate does not vary greatly, but in its
resting state ATP consumption is the same as
exercising muscle - why is it so great?
J P Anderson
 Time window

Function Time
• Loss of consciousness 6-8s
• EEG failure 10 - 12 s
• ATP exhaustion 120 s
• First neuronal damage 5 min
• Severe damage 20 - 30 min
• Infarction 1 - 2 hr
 Intercellular signalling

• Synaptic transmission
• Chemical signalling between nerve cells
• Involves neurotransmitter molecules
• It is a fast process
• Comprises several well defined steps
 Synaptic transmission

1. NT is synthesized and stored in vesicles.

2. An action potential invades the
presynaptic terminal.
3. Depolarization of presynaptic terminal
causes opening of voltage-gated Ca2+
channels.
4. Influx of Ca2+ through channels.
5. Ca2+ causes vesicles to fuse with
presynaptic membrane.
6. NT is released into synaptic cleft via
exocytosis.
7. NT binds to receptor molecules in post-
synaptic membrane.
8. Opening or closing of post-synaptic
channels.
9. Post-synaptic current causes EPSP or
IPSP that changes the excitability of the
post-synaptic cell.
10. Retrieval of vesicular membrane from
plasma membrane.
 Post-synaptic receptors

• Ionotropic receptor
• Activated to open a pore in the membrane
through which ions travel.
• Produces a rapid response.
• Metabotropic receptor
• Activated to produce a series of intracellular
actions involving second messengers via G-
protein activation.
• Slower than ionotropic responses.
Ionotropic receptors
Metabotropic receptors
 Neurotransmitters

• Amino acids
• Glutamate, γ-aminobutyric acid (GABA), Glycine
(Non-essential)
• Amines
• Monoamines
• Acetylcholine, serotonin (5-hydroxytryptamine, 5-
HT), histamine
• Catecholamines
• Dopamine, Noradrenaline, adrenaline
• Purines
• Adenosine, ATP
• Neuropeptides
Amino acid formation

Glycine
Glucose hydroxymethyl
transferase
Pyruvate Serine Glycine

Acetyl CoA

Glut Dehyd Glut Decarb

α-ketoglutyrate glutamate GABA
 Glutamate

• Most common excitatory NT in the brain.

• Mediates the fastest neurotransmission in the
brain.
• 90% of neurones use glutamate as NT and 80
- 90% of synapses in the brain are
glutamatergic.
• Does not enter the brain, thus is synthesized
in the brain.
• Acts on ionotropic receptors
• NMDA
• Kainate
• AMPA
• and metabotropic receptors
Glutamate receptor
 GABA

• Most common inhibitory NT in the brain used

by about a third of neurones.
• Three types of receptors: A and C are
ionotropic, B is metabotropic.
• Site of action for benzodiazepines (valium,
librium) and barbiturates (phenobarbital and
pentobarbital).
 GABA

Glial cell

GABA
Presynaptic breakdown
terminal
Glycine GAT

Glutamate

Glutamic acid
GABA decarboxylase

GABA
VIATT

GABA Postsynaptic
receptors cell
 Glycine

Glial cell
• Major inhibitory NT in
Presynaptic
spinal cord and brain
terminal Glycine
transporter
stem.
Serine
Glucose
• Regulates motor
Serine
neurone activity.
Glycine
hydroxymethyl
transferase • Glycine receptors
inhibited by
strychnine.
VIATT

Glycine Postsynaptic
receptors cell
 Monoamines - acetylcholine

• Widely distributed in CNS.

• Primary NT in parasympathetic division of
the autonomic nervous system.
• Evolved long before synapses - found in
fungi, protozoa and plants.
• Two major divisions of receptor:
• Nicotinic
• Muscarinic
Acetylcholine formation

Glucose

Pyruvate

Acetyl CoA Choline

(Essential Nutrient)

Acetylcholine
Acetylcholine
 Nicotinic

• Ionotropic.
• Fast response (few ms).
• First NT receptor characterized.
• Nicotine’s effects are mediated via this
receptor.
• Blocked by bungarotoxin, cobra toxin and sea
snake toxin.
 Muscarinic

• Metabotropic
• Slow response (100 - 250 ms)
• Activated by muscarine, a poisonous
mushroom derived alkaloid
• Blocked by atropine
 Effect of Acetylcholine

• Vasodilation of vasculature
• Contraction and myosis of iris
• Contraction and accommodation of lens
capillary muscle
• Secretion of saliva and tears
• Slows heart rate
• Increased GI tone and secretions
• Contraction of detrusor muscle and relaxation
of sphincter and bladder
• Sweating
 Sarin gas attack

• Sarin gas bind to part of the

AChE molecule.
• This makes the AChE inactive
and blocks the action of
AChE.
• There is no way to stop the
action of acetylcholine
• Acetylcholine builds up at the
synapse.
• Acetylcholine continues to act.
 Monoamines -serotonin

• Ionotropic (5-HT3) and metabotropic

receptors.
• Formed from tryptophan.
• Serotonergic cell bodies are restricted to the
brain stem.
• Their axons innervate nearly every area of the
brain.
Serotonin formation
 Serotonin

• Implicated in sleep and wakefulness.

• Selective serotonin reuptake inhibitors
(SSRIs)
• Drugs affecting serotonergic neurones treat
depression, anxiety disorders and
schizophrenia
• 5-HT3 antagonists are used to treat
chemotherapy-induced emesis.
Serotonin distribution
 Monoamines - histamine

• Mediates arousal and attention.

• Three types of metabotropic receptor.
• Mediates the allergic reaction.
• Benadryl is an antagonist at central histamine
receptors.
• Antagonists treat motion sickness and GI
disorders.
Histamine formation
Monoamines - histamine
 Catecholamines - dopamine

• Metabotropic receptors.
• Located in the corpus striatum.
• Involved in motivation, reward and
reinforcement.
• Loss of dopamine cells in substantia nigra
causes Parkinson’s disease.
• Antagonists used to induce vomiting.
Catecholamines formation
Catecholamines - dopamine
 Catecholamines - noradrenaline

• Located in locus coeruleus

• Implicated in sleep and wakefulness, attention
and feeding behaviour
• Acts at sympathetic ganglia in PNS
• Acts via α and β adrenoceptors
 Catecholamines - noradrenaline

• Main effects of noradrenaline are peripheral

• β blockers
• Salbutamol
• Adrenaline present in low levels n the brain
• Function unknown
Catecholamines - noradrenaline
Catecholamines - adrenaline
 Purines

• ATP and adenosine

• Receptors widespread in CNS
• One ionotropic, two metabotropic receptors
• Stimulant effects of caffeine and pain are
mediated via these receptors
 Peptide neurotransmitters

• Between 3 and 36 amino acids long

• Include the opioids
• Act via metabotropic receptors
Drugs of abuse

Cocaine •inhibits dopamine uptake

•inhibits dopamine and noradrenaline

Amphetamine uptake

Ecstasy
•reverses direction of serotonin uptake
•releases noradrenaline and dopamine

Heroin •binds to opioid receptors

Cannabis •binds to cannabinoid receptors

LSD •binds to serotonin receptors

 Reading material

• Purves - Chapter 6
• Kandel - Chapter 15
• Bear & Connors - Chapter 6
 Acknowledgement

• Dr Angus Brown, School of Life Sciences,

University of Nottingham UK