Psychodepressants

Question 1

Describe the GABAa receptor

Answer 1

Ligand-gated cl- channel

• pentameric structure, most common being 2a2by
• most commonly found post-synaptically

Question 2

What are the main binding sites of GABAa receptors?

Answer 2

• Direct Agonists/ antagonists eg. GABA -> a-b interface
• Benzodiazepines -> alpha-gamma interface
• Barbiturates -> middle of channel
• Channel blockers eg picrotoxin -> middle of channel
• Channel modulators eg GA -> middle of channel

Question 3

How do barbiturates work?

Answer 3

PAMs that enhance the functional response. They bind in the middle of the channel and keep it open for longer, allowing more cl- in.

Question 4

Why are barbs referred to as dirty compounds?

Answer 4

They act on many different receptors at high concentrations

• Direct GABAa agonist
• Stabilise glycine receptor channel in open form
• nAChR and 5HT3 blockades
• AMPA/Kainate blockade
• Blockade of Ca-dependent NT release

Question 5

When are barbs still used?

Answer 5

Epilepsy, general anaesthetic (very fast onset if needed), euthanasia (easy to OD), and capital punishment (barb is pumped around body by heart and induces sleep)

Question 6

How do Benzos work?

Answer 6

• Bind to alpha-gamma interface on GABAa
• ones that contain a1,2,3,5, as these have a histidine in the binding pocket, rather than 4 and 6, which have arginine
• They increase inhibition to decrease excitation

Question 7

What is the problem with going cold turkey from BZDs and Barbs?

Answer 7

To counteract the increased inhibition by the drugs, our body upregulates excitatory glutamate receptors. Going cold turkey means that there is hyperexcitability, which leads to seizures

Question 8

Describe the GABAb receptor

Answer 8

Metabotropic - Gi/o linked -> decreases cAMP etc -> opens k+ channels -> hyperpolarisation
- Found pre-, post- and extra-synaptically

Question 9

How does GHB work?

Answer 9

• In low concentrations it acts on the GHB receptor to cause an increase in DA release (stimulant - addictive)
• In high concentrations it acts on GABAb receptor to decrease DA release (sedative)
• These effects are heightened with alcohol

Question 10

Describe the NMDA receptor

Answer 10

• Ligand gated cation channel AND voltage gated
• Blocked by Mg/Zn, so glutamate cannot activate it at rest
• The membrane it is in has to be depolarised to repel the Mg out of the receptor, to allow glutamate to activate it.
• Endogenous ligand is glutamate, exogenous is NMDA
• Heterotetrameric structure
• mostly post-synaptic

Question 11

How does Ketamine/PCP work?

Answer 11

• NMDA receptor antagonists - block the channel to directly decrease excitation
• In low concentration, ket just inactivates the NMDA receptors that are on the inhibitory interneurones -> excitatory
• In high concentrations, it causes global inactivation of NMDA receptors -> anaesthetic

Question 12

Why is Ketamine a dirty compound?

Answer 12

• It is also an opioid receptor agonist, an nAChR antagonist, a D2 receptor agonist, and causes monoamine transporter blockade