Neurotransmitters & Their Receptors

Question 1

What is GABA?

Answer 1

The main inhibitory neurotransmitter in the brain
It is synthesised from Glutamate by glutamic acid decarboxylase
Loaded into synaptic vesicles by vesicular inhibitory amino acid transporter

Question 2

What are the two classes of receptors for GABA?

Answer 2

Ionotropic & Metabotropic

GABAa- ionotropic class- 5 different subunits assembled, two alpha, two beeta and a gamma/delta/pi and these assemble to form a chloride channel

GABAb-metabotropic class- g protein coupled receptor, so GABA binds on the outside of the cell, its got transmembrane helices and then the intercellular part interacts with these g proteins and then this activates signalling pathways which acts on channels

GABAa - causes hyperpolarisation through efflux of chloride, going to make the membrane more negative on the inside

GABAb- channels work in a different way, so by causing an efflux of potassium, so this is hyperpolarising and making the cell more negative on the inside

Question 3

What drugs block the activity of GABAa?

Answer 3

Bicuculline & Flumazenil

Question 4

What drugs activate GABAb receptors?

Answer 4

Baclofen - for spasticity (MND, MS treatments)

Question 5

What are GABA reuptake inhibitors and what condition do they help?

Answer 5

Tiagabine/Gabitril

Used for focal seizures

Question 6

What GABA agonist activates GABA receptors and what conditions do they help?

Answer 6

Gabapentin

Used for seizures and neuropathic pain

Question 7

What is Glycine?

Answer 7

The other main inhibitory neurotransmitter
It is synthesied by serine hydroxyl-methyltransferase
Uses VIAAT to be loaded into the synaptic vesicles
Cleared by GlyT

Question 8

What mutation causes hyperekplexia (low tone, exaggerated startle)?

Answer 8

Gly2 mutations

Question 9

What is the result of the poison strychnine acting on Glycine?

Answer 9

Causes excitation and induces seizures

Question 10

What are purines?

Answer 10

E.g. ATP which is an excitatory neurotransmitter in the CNS and PNS
ATP is rapidly catabolised to adenosine

BUT adenosine doesnt meet the full NT criteria

Question 11

Drugs targetting purinergic receptors treat what?

Answer 11

Treatment of chronic pain
Inhibitors of the receptor P2Y12 are anti-platelet agents used for clotting

Question 12

What is dopamine invovled in and what diseases are these linked to?

Answer 12

Movement –> linked to PD
Motivation reward & enforcement –> linked to drug addiction
Cognition & emotion

Schizophrenia

Question 13

Dopaminergic projections

What is the nigro-striatum projection?

Answer 13

Its linked to movement

Cell bodies are localised in the substantia nigra in the midbrain and project to the striatum and in particular the putamen

Question 14

Dopaminergic projections

What is the Mesolimbic projection?

Answer 14

It linked to reward and addiction

From the midbrain part of the limbic system, so from the ventral midbrain or ventral tegmentum area to the nucleus accumbens

Question 15

Dopaminergic projections

What is the Mesocortical projection?

Answer 15

Its linked to cognition, emotion and motivation

Going from the midbrain but then projecting extensively throughout the cortex so in limbic structures like the cingulate gyrus and also extensively throughout the frontal cortex too

Question 16

Which two enzymes break dopamine down?

Answer 16

MAO (monoamine oxidase) and COMPT (catechol-O-methyltransferase)

Question 17

How are MAO and COMPT used in PD?

Answer 17

MAO-B inhibitors are given to PD patients before they are put on L-Dopa and can also be used in combination with L-Dopa later in the disease

COMPT inhibitors are my typically used in combination with L-Dopa to manage the symptoms of PD

Question 18

What are the 2 classes of dopamine receptors?

(all dopamine receptors are metabotropic)

Answer 18

D1-like - D1 and D5 receptors
D2-like- D2, D3 and D4 receptors

D1-like couple via Gs which is a stimulatory G protein
D2-like couple via Gi whihc is an inhibitory G protein

Question 19

What is the main place in whihc neuroadrenaline neurons are located?

Answer 19

In the locus coeruleus in the midbrain

Question 20

What is the main place in which adrenaline is located in the brain?

Answer 20

Cell bodies are localised in the brain stem

Question 21

What do beta blockers act on?

Answer 21

They act on beta adrenergic receptors and can be used to treat cardiac arrhythmias and migraines as well

Question 22

Can antihistamines cross the BBB?

Answer 22

Yes

e.g. Promethazine crosses the BBB and targetes H1 receptors making it a powerful sedative

Question 23

What drugs target the serotonin system?

Answer 23

Many antidepressants and anxiolytics act by increasing the serotonin system

SSRI act on serotonin transporters–> by blocking these we reduce the uptake of serotonin from nerve terminals and increase serotonin leveles and serotonergic transmission

But too much prozac e.g. in excess serotonergic agonism a.k.a. serotonin syndrome, can be bad, causing mild shivering & diarrhea to severe rigidity, fever & seizures

Loss of serotonergic neurons is an additional feature of PD

Question 24

What are some agonists/antagonists targetting 5-HT (serotonin) and what do they treat?

Answer 24

Sumatriptan (agonist) –> treats migraines
Ondansetron(antagonist) –> treats nausea/vomitting from chemotherapy
Fenfluramine (antagonist) –> suppresses appetite

Question 25

What are some of the functions of peptide neurotransmitters?

Answer 25

Pain –> substance P & opioid peptides
Stress responses –> CRH/CRF
Food intake –> NPY, melanocortins
Pituitary peptides –> vasopressin, oxytocin