GABA & Glutamate

What makes GABA distribution different to most other NTs

GABA is widely and uniformly distributed throughout the brain

This is in contrast to most other neurotransmitters which have a

localised, discrete distribution (e.g. acetylcholine, noradrenaline, dopamine and serotonin)

In GABA transmission, what is taken into the neuron, how?

Glutamate via carrier mediated transport

How does Glutamate become GABA

Glutamate —(glutamic acid decarboxylase)-→ GABA

GABA is actively packaged into vesicles by an specific transporter & is released via what mechanism

classical Ca2+ -mediated exocytosis

Termination of GABA is via what

uptake by a GABA transporter

Degradation of GABA is via what

Degradation is via GABA transaminase

GABA exerts its effects via how many subtypes of receptor?

Name them

2 main subtypes

GABA_A and GABA_B receptors

GABA_A receptors are permeable to what

Cl-

Name the 5 binding sites on GABA_A receptors & when their ligand binds do they enhance/inhibit

GABA binding site - agonists/antagonists can bind here

Benzodiazepine binding site - enhance the actions of GABA

Barbiturate binding site - enhance the actions of GABA

Neurosteroid binding site - enhance the actions of GABA

Picrotoxin binding site - blocks the Cl- channel

True/False GABA transmission is always inhibitory

True - GABA is the main inhibitory transmitter in the brain

GABA is required for what functions

General CNS depression (not the mood disorder)/inhibition

Regulates/modulates the activity of other neurotransmitter systems

What makes Glutamate distribution different to most NTs

Glutamate is widely and uniformly distributed throughout the brain

This is in contrast to most other neurotransmitters which have a localised, discrete distribution (e.g. acetylcholine, noradrenaline, dopamine and serotonin)

In Glutamate transmission, what is taken into the neuron, how?

Glutamine is taken into the neuron via carrier mediated transport

What converts glutamine → Glutamate

Glutamine —(Glutaminase)→ Glutamate

Glutamate is actively packaged into vesicles by an specific transporter & is released via what mechanism

Release is via classical Ca2+ - mediated exocytosis

How is glutamate terminated & degraded

Termination is via uptake by a glutamate transporter

Degradation is via glutamine synthase

Glutamate exerts its effects via 4 main subtypes of receptor - name them

NMDA, AMPA, kainate and metabotropic receptors

Important

What is unique about the ions that NMDA receptor is permeable to

permeable to Na+, Ca2+ and K+

Ca2+ permeability here is important

Name the 3 inhibitory sites on NMDA receptors

Mg2+ site - channel is normally blocked by Mg2+ when the cell is normally polarised but is overcome when the cell is depolarised

Zn2+ site - binding of Zn2+ inhibits receptor opening

Channel blocking drug site - certain drugs (e.g. PCP selectively block the channel)

Is Glutamate excitatory/inhibitory

Glutamate is the main excitatory transmitter in the brain

EPSP: Excitatory post-synaptic potential

Glutamate is required for what functions

General CNS excitation/activation

Regulates/modulates the activity of other neurotransmitter systems

In what 2 treatments is the glutamate receptor used

Head injury and stroke - A major drug target is the development of glutamatergic antagonists to reduce excitotoxic brain damage following head injury and stroke

Epilepsy - Some anti-epileptic drugs work by antagonizing glutamate receptors, specifically the AMPA subtype (e.g. perampanel)

Epilepsy is a ______ disorder characterised by what

neurological disorder characterised by seizures

What causes seizures

episodic high-frequency discharge of a group of neurons in the brain

Where in the brain do seizures happen

Can happen in any region - usually starts locally, but then spreads to other areas of the brain

The symptoms depend on the region of the brain affected

Prevalence of epilepsy (%)

0.5-1% are affected

In most cases of epilepsy , there is no recognisable cause, but 2 possible causes could be

After brain damage (trauma, infection, tumours)

In certain inherited neurological disorders

Name & differentiate these 4 types of epilepsy

What happens in the tonic phase of tonic-clonic seizures

An initial strong contraction of the whole musculature

Rigid extensor spasm

Respiration may stop

Defecation, micturition and salivation may occur

What happens in the clonic phase of tonic-clonic seizures

A series of violent synchronous jerks

How long does the clonic phase last

2-4 minutes

After what phase does the patient regain consciousness after tonic-clonic seizures & in what state are they

Patient recovers consciousness feeling ill and confused after the clonic phase

What happens in absent seizures

The patient abruptly stops whatever he or she was doing and stares vacantly for a few seconds

The patient is unaware of his or her surroundings

In what state do people recover from absent seizures

They recover abruptly with little after-effects

What age group is most affected by absent seizures

Children

which one of these represents an EEG of a tonic-clonic seizure or an absent seizure

Top = absent

Bottom = tonc-clonic

Describe the tonic-clonic seizure EEG

1 – normal discharge, 2 – tonic phase, 3 – clonic phase, 4 – post-seizure coma

Describe the EEG pattern of absence seizures

EEG pattern reflects neural oscillations between thalamus and cortex and is due to T type calcium channels

Describe the neurochemical basis underlying seizures (glutamate, GABA, electrical properties)

- Enhanced excitatory amino acid (glutamate) transmission

- Reduced inhibitory amino acid (GABA) transmission

- Abnormal electrical properties of the affected cells

Risk associated with repeated epileptic seizures

Repeated epileptic discharge can cause neuronal death through excitotoxic mechanisms

Name a form of epilepsy that is associated with neurodegeneration

Lennox-Gastaut syndrome is a particularly severe form of epilepsy that affects children. It is associated with progressive mental retardation which probably occurs as a result of neurodegeneration.

Antiepileptic/Anti-convulsant drugs are fully effective in treating seizures in what % of patients

50-80%

Name the 4 main long-established anti-epileptic drugs

Phenytoin

Carbamazepine

Valproate

Ethosuximide

(others include Barbituates (e.g. phenbarbital) & Benzodiazepines (e.g. diazepam, clonazepam, lorazepam))

By what 4 mechanisms do anti-epileptic drugs control abnormal discharge

- Enhancement of GABA action

- Inhibition of voltage-gated sodium channel function

- Inhibition of voltage-gated calcium channel function

- Antagonism of glutamate receptors

Aim of anti-epileptic treatment

Prevent abnormal discharge whilst leaving normal discharge intact

Some anti-epileptic drugs work by enhancing GABAergic transmission. Give 3 mechanisms by which this would work & name a drug for each mechanism

- Positive allosteric modulation of the GABA_A receptor (e.g. barbituates and benzodiazepines)

- Inhibition of GABA transaminase (e.g. vigabatrin)

- Inhibition of GABA uptake (e.g. tiagabine)

How do Benzodiazepines enhance GABAergic transmission

Benzodiazepines bind to the GABAA receptor at a different site to GABA and increase the affinity of GABA for the receptor

Mechanism of action of phenytoin, carbamazepine, valproate & lamotrigine

Inhibiting voltage-dependent sodium channel function thereby reducing neuronal membrane excitability → prevents propagation of action potentials

Phenytoin, carbamazepine, valproate & lamotrigine blocking action shows the phenomenon of use dependence - explain

They preferentially block the excitation of neurons that are firing repetitively)

They preferentially bind to the inactivated state of the Na + channel

Valproate can work by inhibiting voltage-dependent sodium channel function or ….

inhibiting T-type voltage-gated calcium channel function that underpins absence seizures

What other anti-epileptic drug (other than valproate) works by inhibiting T-type voltage-gated calcium channel function that underpins absence seizures

Ethosuximide

How do gabapentin and pregabalin work as anti-epileptic drugs

They work by binding to a subunit of P/Q-type voltage-gated calcium channels thereby preventing it from trafficking to the membrane. This reduces calcium dependent exocytosis of synaptic vesicles.

How does perampanel work as an anti-epileptic drug

By antagonizing glutamate receptors, specifically the AMPA subtype

5 elements of normal fear response to threatening stimuli

- Defensive behaviours

- Autonomic reflexes

- Arousal & alertness

- Corticosteroid secretion

- Negative emotions

Name & explain 6 clinically recognised anxiety disorders

Generalised anxiety disorder (ongoing state of anxiety with no clear reason)

Social anxiety disorder (fear of being/interacting with other people)

Panic disorder (attacks of overwhelming fear in association with marked somatic symptoms – sweating, tachycardia, chest pains, trembling, choking etc.)

Obsessive compulsive disorder (compulsive ritualistic behaviour driven by irrational anxiety)

Phobias (strong irrational fears of specific things or situations)

Post-traumatic stress disorder (anxiety triggered by insistent recall of past stressful experiences)

Main type of anxiolytic drugs

Benzodiazepines (e.g. diazepam (Valium®); alprazolam (Xanax®)

Anxiolytic drugs can also be drugs used to treat other things give 5 examples

1) Some drugs used for depression (e.g. SSRIs such as fluoxetine (Prozac®))

2) 5-HT1A receptor agonists (e.g. buspirone)

3) Beta-adrenoceptor antagonists (i.e. beta-blockers such as propranolol)

4) Some drugs used for epilepsy (e.g. gabapentin, pregabalin etc.)

5) Some drugs used for schizophrenia (e.g. olanzapine, risperidone etc.)

Name the 4 types of benzodiazepines & give 2 examples of each

Ultrashort duration

- *Midazolam

- *Zolpidem (Ambien®) (not strictly a benzo, but similar MoA)

Those 2 are mainly used as hypnotics - sleeping pills)

Short duration

- Lorazepam

- Temazepam

Medium duration

- Alprazolam

- Nitrazepam

Long duration

- Diazepam (Valium®)

- Chlordiazepoxide

Name 5 pharmacological effects of benzodiazepines

Reduction of anxiety and aggression -  useful for acute anxiety states, behavioural emergencies, certain medical, surgical and dental procedures

Sedation and induction of sleep -  useful for transient/acute causes of sleep disturbance such as jet lag, emotional upse

Reduction of muscle tone and coordination

Anticonvulsant effects - useful for epilepsy including life-threatening status epilepticus

Anterograde amnesia - prevent formation of memories of events experienced while under their influence. (Flunitrazepam (Rohypnol®); the “date-rape” drug)

True/False Benzodiazepines can’t be taken for a long time

True - only recommended for short durations as tolerance/dependence can occur, as well as rebound insomnia