pharma lecture 8

Name the two excitatory amino acid transmitters.

Glutamate and aspartate

Name the two inhibitory amino acid transmitters.

Glycine and GABA (gamma-aminobutyric acid)

What do EPSP and IPSP stand for?

Excitatory Post-Synaptic Potential and Inhibitory Post-Synaptic Potential

What happens during an EPSP?

Depolarisation – Na⁺ channels open, Na⁺ moves in

What happens during an IPSP?

Hyperpolarisation – Cl⁻ ions move in OR K⁺ ions move out

What is the typical resting membrane potential of a neurone?

-70 mV

What is the threshold for action potential generation?

Around -50 to -55 mV (depolarisation to threshold triggers AP)

Where is glutamate distributed in the nervous system?

Widely distributed in the CNS

How is glutamate stored and released?

Stored in synaptic vesicles; released by Ca²⁺-dependent exocytosis

What is the glutamate-glutamine cycle?

Glutamate is taken up into nerve terminals via EAAT (Excitatory Amino Acid Transporter) and converted to glutamine (Gln)

What does EAAT stand for?

Excitatory Amino Acid Transporter

What are the three ionotropic glutamate receptors?

AMPA, Kainate, and NMDA

What does AMPA stand for?

α-amino-3-hydroxy-5-methyl-isoxazole

What does NMDA stand for?

N-methyl-D-aspartate

How many metabotropic glutamate receptors (mGlu) are there?

8 (mGlu1-8)

Where are metabotropic glutamate receptors located?

Pre- and postsynaptically

What are the characteristics of AMPA receptors?

Fast kinetics, wide distribution, cations enter neurone → depolarisation

What are the characteristics of Kainate receptors?

Fast kinetics, restricted distribution, cations enter neurone → depolarisation

Which has wider distribution – AMPA or Kainate?

AMPA

What are the characteristics of NMDA receptors?

Slow kinetics, wide distribution, co-localised with AMPA, permeable to cations (especially Ca²⁺)

What two substances are required for NMDA receptor activation?

Glutamate and glycine

What is the voltage-dependent Mg²⁺ block of NMDA receptors?

At resting membrane potential, Mg²⁺ blocks the channel; depolarisation removes the Mg²⁺ block

What is the modulatory (+) site on NMDA receptors?

Polyamines (e.g., spermine)

Why does glutamate release only activate AMPA receptors at normal resting potential?

Because the NMDA receptor is blocked by Mg²⁺ at resting potential

What happens when the neurone is depolarised?

Mg²⁺ is expelled from the NMDA channel, allowing Ca²⁺ entry

How does glycine facilitate NMDA response?

Glycine is a co-agonist required for NMDA receptor activation

What is LTP?

Long Term Potentiation – involved in memory

What three changes occur during LTP?

1) Increased glutamate release (presynaptic), 2) Increased synapse growth (pre and postsynaptic), 3) Increased AMPA receptors (postsynaptic)

What is quisqualate?

An AMPA receptor agonist

What are the three groups of metabotropic glutamate receptors?

Group 1 (mGlu1, mGlu5), Group 2 (mGlu2, mGlu3), Group 3 (mGlu4, mGlu6, mGlu7, mGlu8)

What are the properties of Group 1 mGlu receptors?

Postsynaptic, excitatory, Gq-coupled

What second messenger system do Group 1 mGlu receptors activate?

PLCβ → PIP2 → IP3 + DAG → ↑Ca²⁺ release and PKC activation

What are the properties of Group 2 and Group 3 mGlu receptors?

Presynaptic, inhibitory, Gi/Go-coupled

What second messenger system do Group 2 and 3 mGlu receptors inhibit?

Adenylyl cyclase → ↓cAMP

What is the overall effect of mGlu2/3/4/6/7/8 activation?

Inhibitory – reduce neurotransmitter release

What is excitotoxicity?

Neuronal cell death caused by excessive glutamate release and excessive Ca²⁺ influx

What triggers excitotoxicity in ischaemia (stroke)?

Depolarisation → release of large amounts of glutamate

What are the five mechanisms by which glutamate causes ↑[Ca²⁺]i in excitotoxicity?

1) AMPA receptor stimulation (depolarisation), 2) Unblock of NMDA receptors (Ca²⁺ influx), 3) Metabotropic receptor contribution, 4) Opening of voltage-gated Ca²⁺ channels, 5) Increased Na⁺/Ca²⁺ exchange

What happens when [Ca²⁺]i becomes too high

Activation of proteases and lipases → membrane damage; activation of NOS → NO + ROS → free radical damage → cell death

What three conditions are associated with NMDA receptor overactivation?

Brain damage following stroke, epilepsy, Alzheimer's disease

What are the two NMDA receptor drugs in clinical use?

Ketamine (anaesthesia/analgesia) and Memantine (Alzheimer's)

What is perampanel?

An AMPA receptor antagonist used as an antiepileptic

What is the main inhibitory transmitter in the brain

GABA (gamma-aminobutyric acid)

Where is GABA found?

Brain tissue only

How is GABA synthesised?

From glutamate via the enzyme glutamic acid decarboxylase

How is GABA removed from the synapse?

Via the GAT-1 transporter (GABA transporter)

What type of receptor is GABAᴀ?

Ionotropic – selectively permeable to Cl⁻ → hyperpolarisation → fast synaptic inhibition (IPSP)

What does GABAᴀ activation reduce?

The depolarisation mediated by excitatory signalling

What type of receptor is GABAʙ?

Gi/Go-protein coupled receptor

What are the presynaptic effects of GABAʙ activation?

Inhibit voltage-gated Ca²⁺ channels → reduced transmitter release

What are the postsynaptic effects of GABAʙ activation?

Open K⁺ channels → hyperpolarisation → reduced neuronal excitability

What does GABAʙ activation inhibit?

Adenylyl cyclase (↓cAMP)

Name three drug classes that enhance GABAᴀ receptor function.

Benzodiazepines, anaesthetics, barbiturates

What are the clinical uses of benzodiazepines?

Sedative, anxiolytic, anticonvulsant

What is muscimol?

A GABAᴀ receptor agonist – causes hallucinations

What is bicuculline?

A GABAᴀ receptor antagonist – causes convulsions

What is picrotoxin?

A GABAᴀ channel blocker – causes convulsions

What is baclofen and what is it used for?

A GABAʙ receptor agonist (lipophilic, crosses BBB) – used to treat spasticity (increased muscle tone)

What is epilepsy?

Seizures caused by high frequency discharge of cerebral neurones

What may cause a GABA deficit?

Prolonged seizures can cause excitotoxicity and neuronal death

What are the three main targets of antiepileptic drugs?

GABAergic transmission, Na⁺ channels, Ca²⁺ channels

What is vigabatrin and how does it work?

An anticonvulsant that inhibits GABA re-uptake or metabolism

Where is glycine the main inhibitory transmitter?

In the spinal cord

What type of receptor does glycine act on?

Ligand-gated Cl⁻ channel (ionotropic)

What blocks glycine receptors?

Strychnine (causes convulsions – a convulsant poison)