L11 - GABA

Question 1

Is glycine inhibitory or excitatory?

Answer 1

Both

Question 2

Are GABA R found pre or postsynaptically?

Answer 2

Both

Question 3

GABA makes up _% NT in the brain, glutamate makes up _%

Answer 3

25, 50

Question 4

GABA A/B/C, which are ionotropic, which are metabotropic?

Answer 4

A and C are ion. B is metab

Question 5

Benzodiazepines and Glutamate modulators can have similar actions if you can manipulate their receptors

Answer 5

Anxiolytic, muscle relaxant, anticonvulsant, sedative, anaesthetic, drug withdrawal, amnesic

Question 6

GABA has a __ conc, with a _____ distribution in the brain. Unlike amine, GABA precursors come from?

Answer 6

Mm, distinct (more conc in some parts than others), cellular metabolic pool

Question 7

2 types of GABAergic neurons

Answer 7

1) In cortex: local circuit interneurones
Acts as inhib. constraints over Glu projections
2) Longer projections in other brain regions
e.g. striato-nigral in motor cortex

Question 8

Compare % of neuronal re-uptake for GABA and Glutamate

Answer 8

GABA – 50, Glu – 100

Question 9

GABA A Receptors – subunits? Which subunit is essential for forming Cl- channels?

Answer 9

Hetero-pentameric (5 subunits per receptor, not all the same)
*Alpha is essential for forming anion (Cl-) channel (+ve a.acids near ends of ion channel)

Question 10

List 4 types of drugs that potentiate the GABA A receptor

Answer 10

1) Benzodiazepines – Diazepam, flumazenil
2) Barbituates – pentobarbitone
3) Neurosteroids – alphaxalone
4) Anticonvulsants – tiagabine, vigabatrin

Question 11

List 3 drugs that inhibit GABA A receptor

Answer 11

1) Bicuculline – decrease GABA binding
2) Picrotoxin – binds in pore, prevents Cl- flux
3) Penicillin – open channel blocker
* ALL these compounds, if in high enough doses = seizures

Question 12

List a drug that activates GABA A receptors

Answer 12

Muscimol aka magic mushroom (hyperpolarises) – hallucinogen

Question 13

Benzodiazepines (BZ) are positive/negative allosteric modulators of fast inhibitory transmission by GABA at GABA A receptors

Answer 13

Positive *no effect without agonist (GABA) activity
* A positive allosteric modulator (PAM) or allosteric enhancer induces an amplification of the orthosteric agonist’s effect, either by enhancing the binding affinity or the functional efficacy of the orthosteric agonist for the target protein

Question 14

BZ bind to the _ subunit of receptor but binding is affected by _ and _ subunits

Answer 14

Gamma, alpha, beta

Question 15

Actions of BZ

Answer 15

Anxiolytic, sedative-hypnotic, anticonvulsant, muscle relaxant

Question 16

BZ clinical efficacy similar/vary but pharmacokinetics similar/vary

Answer 16

Similar, vary

Question 17

BZ speed of onset determined by? Duration of action dependent upon?

Answer 17

Lipid solubility, metabolism

Question 18

Longer acting BZ can form?

Answer 18

Active metabolites

Question 19

Half-life of BZ can vary from _ hours to _ hours

Answer 19

1-90

Question 20

Barbituates vs BZ – which one increases opening time and which one increases probability of opening?

Answer 20

Barb increases opening time

BZ increases prob

Question 21

Barbiturates binds at _ subunits, increase/decrease Cl- channel open time, blocks ____ receptors

Answer 21

Alpha, increase, AMPA

Question 22

GABA B receptors are G_ receptor, sometimes co-localised with ____

Answer 22

Gi, GABA A

Question 23

When GABA B is presynaptic it _____, when postsynaptic it ____

Answer 23

Pre: inhibit NT release
Post: Slows hyperpolarization

Question 24

!GABA B agonist and antagonist

Answer 24

Ag: Baclofen – acts in spinal cord to reduce muscle spasm and treats alcholics
Antag: Saclofen

Question 25

Physiological roles of GABA B unclear but linked to?

Answer 25

Respiration

Question 26

Gamma Hydroxy Butarate (GHB) relationship with GABA

Answer 26

Closely related to GABA (GHB doesn’t have the amino but has a hydroxyl instead)

Question 27

Is GHB a precursor or metabolite of GABA?

Answer 27

Both

Question 28

GHB uses

Answer 28

Anaesthetic, body building, treatment of alcohol dependence, narcolepsy, insomnia, depression

Question 29

!GHB receptors are ion/metab and has the effect of?

Answer 29

Metab, Gi, inhibits release of GABA and Glu

Question 30

GHB is a partial agonist at?

Answer 30

GABA B receptors (some receptors have low, some have high affinity) - Effect of GHB likely due to GABA synthesis - GHB: At increasing concentrations: euphoria, anxiolysis, disinhibition

Question 31

GABA C receptors – ion/metab? How many subunits? Affinity compared to GABA A

Answer 31

-Ion, single, higher

Question 32

T/F: GABA C is blocked by bicuculline or modulated by steroids, barbiturates or benzodiazepines

Answer 32

F

Question 33

GABA C antagonist aids in

Answer 33

Inhibiting myopia development and facilitates learning and memory

Question 34

GABA Transporters – 3 subtypes

Answer 34

1 neuronal, 2 present in neurones and glia

Question 35

GAT-1 blocked by what drug? How does it work?

Answer 35

Tigabine (anticonvulsant, useful in PTSD, neuropathic pain, tonic spasms in MS) -It decreases GABA uptake by neuronal and extraneuronal tissues

Question 36

Vigabatrin

Answer 36

Irreversible inhibitor of GABA transaminase. Potential to cause psychiatric disorders (depression and psychosis)

Question 37

Gabapentin

Answer 37

Developed as GABA analogue. Increases release of GABA by unknown mechanism

Question 38

There is more glycine in spinal cord than the brain. In the spinal cord, higher amounts of glycine found in?

Answer 38

Medulla

Question 39

What blocks the action of Glycine? GABA?

Answer 39

Strychnine, Bicuculline

Question 40

Gly receptor subunits?

Answer 40

Pentameric, alpha (4 cloned), beta subunits

Question 41

What effect does tetanus toxin have on Gly release?

Answer 41

Blocks it, leads to reflex hyper excitability and muscle spasm

Question 42

``` GLYT1 = astrocytic/neuronal GLYT2 = astrocytic/neuronal ```

Answer 42

1 - A 2- N