pharm & toxico sec 10

What's the main inhibitory transmitter in the brain?

GABA

What is Gaba made from?

formed from glutamate by GAB (found ONLY in the synthetizing neurons)

What are 2 GABA receptor and their corresponding receptor type?

GABA a receptor: Ligand-gated chloride channel

GABAb receptor: G-protein coupled receptor.

What is the particularity of GABA receptors?

They are both inhibitory.

What structural class does GABAa receptor belongs to?

Same class as nicotinic acetylcholine receptors

where are GABAa receptor located and what do they mediate?

Location: Postsynaptic

Fast inhibition

characteristics of GABAa receptor

permeable to Cl-

Reduces post synaptic excitability

Agonist that interacts with GABA

Muscimol

Diazepam

Pentobarbital

muscinol agonist

served from hallucinating mushroom

Binds to receptor site

No therapeutic use

diazepam agonist

binds to benzodiazepine modulatory site

Enhances the action of GABA

Used as sedative

pentobarbital agonist

channel modulator

Enhances GABA

sedative

Benzodiazepine action

increases affinity for GABA on receptor

0 effect on glutamate / glycine channels

Antagonist of GABAa receptor

bicuculline

Flumazenil

Picrotoxin

how does channel blockers work on GABAa? picrotoxin

binds to the channel and blocks the channel

where is glycine found?

spinal cord

What does glycine receptor resemble to and why?

GABAa bc it is multimeric ligand-gated chloride channel

What are the specificities of bacterial toxins onto glycine receptors?

prevents glycine release form inhibitory interneurons in spinal cords

causes reflex hyperexcitability / muscles spasms

Characteristics of 5HT?

(serotonin)

neurotransmitter in the brain

all are GPCR except for 5HT3 = ligand-gated channel.

can be excitatory / inhibitory

5-HT biosynthesis

Tryptophan -> 5-hydroxytrophan -> 5-hydroxytriptamine

Characteristic of 5-HT1?

Inhibitory on brain

vasoconstriction

decrease cAMP

Characteristic of 5-HT2?

excitatory effect

increase of IP3/DAG

Characteristic of 5-HT3?

excitatory effect

ligand-gated cation channel

Characteristic of 5-HT4?

excitatory effect

increase of cAMP

How does SSRIs work onto the serotonin neuron?

the serotonin will go through the serotonin transporter. Then, the SSRI would bind to the serotonin transporter blocking it. the serotonin will then bind to the serotonin receptor.

what type of toxin can go through CNS and why ?

small, non-polar because they can pass the BBB

What is a neurotransmitter?

chemical released by PREsynaptic terminals producing excitatory/ inhibitor responses in POSTsynaptic neurons

2 types of neurotransmitters:

- fast neurotransmitters

- slow neurotransmitters

What does fast neurotransmitter act on?

ligand-gated ion channels

e.g. GABA, glutamate

What does slow neurotransmitters and neuromodulators act on?

C-protein coupled receptors

e.g dopamine, 5HT (serotonin)

excitatory neurotransmitter

AP potential occurs, and excitatory neurotransmitters are released.

Neurotransmitters bind with channel, opening it.

Ions flows to the postsynaptic neuron and release the AP to the following neuron

inhibitory neurotransmitter

AP potential occurs, and inhibitory neurotransmitters are released.

Neurotransmitters bind with channel, opening it.

Ions flows to the postsynaptic neuron

hyperpolarization = reduces action potential

What can drug have an effect on in the CNS?

receptors, transmitter release/ reuptake

2 main amino acid neurotransmitters in CNS:

L- glutamate

GABA

What is the principal excitatory transmitter

L-glutamate

What is the principal inhibitory transmitter

GABA

Where does the Glutamate come from in the CNS?

from glucose / glutamine synthesized in the glial cells ( astrocytes)

What are the 4 main glutamate receptor subtypes?

AMPA / kainate

NMDA

AP-4 (metabotropic)

What are the properties of AMPA/ Kainate?

mediate fast excitatory synaptic transmission in the CNS

Na+ cation channel

What are the properties of NMDA?

Plays role in long-term changes in the brain

= learning & memory/excitotoxicity

Ca2+ cation channel

What are the properties of AP-4?

G-protein couple receptors modulate synaptic transmission

NMDA receptor is permeable to _______ and blocked by __________ and it is dependent on __________

1) Ca2+

2) Mg2+

3) voltage

what does the activation of NMDA receptor require?

glycine and glutamate

what is the role of glycine in NMDA?

antagonist, inhibition of glutamate

what are the characteristics of anaesthetic drugs onto NMDA receptor?

blocking the channel

what is the consequence of high glutamate concentration?

it enhances the glutamate-receptor activity resulting in brain damages

mechanism of cell damage in the brain by GLUTAMATE

1) interruption of blood flow to the brain -> depolarization of glutamate -> release of neurons

2) releases the glutamate activating on AMPA, NMDA and metabotropic receptors

3) Activation of receptors causes calcium ion accumulation/ neurotoxicity

4) activation of proteases and lipases -> membrane damage

5) activation of NO synthase. No in high concentration can damage membrane lipids.

Explain the mechanism of excitotoxicity.

1) depolarization caused by interruption of blood flow

2) Glutamate gets secreted and binds to AMPA receptors and lets Na+ through the postsynaptic neuron = depolarization unbinds the Mg 2+ on the NMDA receptor and binds the Na+ molecule opens the Ca2+

3) increase the Ca2+ concentration -> cell damage

4) glutamate binds with the metabotropic receptor increases IP3