Psychodepressants

Question 1

Psychodepressants and receptors primarily responsible for mediating their effects:

Answer 1

GABAA receptor:
BARBITURATES
BENZODIAZEPINES

GABAB receptor:
GBL/GHB

NMDA receptor:
KETAMINE (AND PCP)

Question 2

GABA- recap (3)

Answer 2

-The major inhibitory neurotransmitter in the central nervous system (CNS)

-Approx one-third of synapses in the CNS utilises GABA as their inhibitory neurotransmitter

-Activate ligand-gated ion channel (GABAA) and G-protein coupled (GABAB) receptors

Question 3

What is the function + target of GABAA?

Answer 3

Important roles in mediating inhibitory neurotransmission in local circuit interneurons

GABAA receptor a key drug target for anxiety disorders and insomnia (amongst other conditions)

Question 4

Recap of the GABAA receptor

Answer 4

Six ᵷ subtypes (ᵷ 1–6)
Three ᵷ subtypes (ᵷ 1-3)
Three ᵷ subtypes (ᵷ 1-3)
Also δ ε π θ subunits

Multiple binding sites:
- Agonists/antagonists e.g. GABA
- Benzodiazepine binding site
- Channel blockers e.g. picrotoxin
- Channel modulators e.g. GA
- Allosteric modulators e.g. barbiturates

Question 5

Barbiturate and benzodiazepine binding sites (4)

Answer 5

• Each GABAA receptor subunit comprised of four transmembrane domains (M1-M4)
• Central channel lined by five a-helical M2 segments of each subunit – this is surrounded by an outer ring of alternating M1 and M3segments – M4 segments are a component of the outer ring

Benzodiazepines interact with the
extracellular a1–gamma2 interface.

Barbiturates proposed to interact w/ the M2 and M3 β-subunit domains – the β-subunit shown to be sufficient for binding.

Question 6

An introduction to barbiturates (5)

Answer 6

A class of GABAA receptor positive allosteric modulators that are no longer recommended as anxiolytics and hypnotics.

Barbiturates increase the activity of GABAA receptors –binding increases channel opening beyond that seen with GABA alone to enhance functional response

Responsible for severe depressant effect on the central nervous system (CNS):

inc. Inhibition
dec. Excitation
* inc. direct GABAA agonist
* Glycine receptor – stabilises open channel
* nAChR & 5-HT3 receptor blockade
* AMPA/kainate receptor blockade

Barbiturates are still used for:
Epilepsy:(e.g., phenobarbital)
General anaesthesia: (e.g., sodium thiopental)

Question 7

Barbiturates and capital punishment (4)

Answer 7

Sodium thiopental:

• lethal injections in US in high doses
• Truth serum in lower doses
• used in assistive suicide

Question 8

An introduction to benzodiazepines (6)

Answer 8

• Benzodiazepines bind to a distinct regulatory site on GABAA receptors

*Benzodiazepines stabilise the GABAA receptor binding site for GABA in the open configuration

*Benzodiazepines therefore increases GABA affinity for its binding site and produces a general enhancement of its neuroinhibitory actions

Benzodiazepines are therefore classed as positive allosteric modulators

Benzodiazepines are “cleaner” compounds compared to the barbiturates – do not activate other receptors (e.g. glycine, glutamate receptors)

Antidote available – flumazenil is a competitive antagonist at the benzodiazepine binding site

Question 9

Benzodiazepine duration of action

Answer 9

table

Question 10

Relative drug harm and dependence

Answer 10

data

Question 11

Barbiturates, benzodiazepines and addiction

Answer 11

Barbiturates and (to a lesser extent) benzodiazepines are associated with unwanted side-effects (e.g., amnesia) and can induce tolerance and withdrawal symptoms

images

Question 12

recap of the GABAB receptor (3)

Answer 12

GPCR

Dimers: Heteromers GABAB1 & GABAB2

IMAGES

Question 13

intro to GHB + GBL (2)

Answer 13

γ-hydroxybutyrate (GHB) was first synthesised as an anaesthetic agent – it was subsequently discovered that GHB is a short-chain fatty acid that occurs naturally in the brain and acts as a neurotransmitter and neuromodulator

γ-butyrolactone (GBL) is a precursor of GHB that, when ingested, is rapidly metabolised into GHB, exerting the same clinical effects as GHB γ-butyrolactone (GBL)

images

Question 14

GHB use and abuse

Answer 14

use= anaesethesia (1960s)
abuse= Party drug

use=na+ oxybate for narcolepsy w/attacks of cataplexy
abuse= date rape drug

Question 15

GHB MoA 1 -GHBr + GABAbr (6)

Answer 15

GHB receptor:
* G-protein coupled receptor (GPCR)
* GHB acts as a high affinity, full agonist

GABAB receptor:
* G-protein coupled receptor (GPCR)
* GHB acts as a low affinity, full agonist

Endogenous concentrations of GHB too low to activate GABAB receptors

However, when concentrations of GHB in the brain rise (e.g., drug use), the GHB receptor desensitises and GHB acts as a competitive agonist at pre-synaptic GABAB receptors

GHB receptor: dec. stim. DA release (stim. effects)

GABAB receptor: inc. inhib. DA release (sedative effects)

Question 16

GHB MoA 2 (4)

Answer 16

As a result of its “dual” mechanism of action:
* GHB initially causes an increase in dopamine secretion due to the activation of GHB receptors

• At increasing concentrations, GHB can subsequently inhibit dopamine secretion due to the activation of GABAB receptors

Increasing concentrations of GHB can inhibit the mesocortical pathway, which has important
roles in:
* Cognitive control
* Motivation
* Emotion

Question 17

recap on the NMDA receptor

Answer 17

Three subunit types (plus alternate splice variants):
* GluN1 (or NR1)
* GluN2 (or NR2)
* GluN3 (or NR3)

Hetero-tetrameric
“Dimer of dimers”

Question 18

intro to ketamine and PCP (2)

Answer 18

Phencyclidine (PCP) is a non-competitive antagonist of the NMDA receptor with
anaesthetic and analgesic properties – associated with prolonged emergence delirium

Ketamine is a structural analogue of phencyclidine (PCP) – associated with:
- a lower potency,
- shorter duration of action and
- lower incidence of adverse emergence effects

Question 19

Ket use + abuse

Answer 19

use= anaesthesia
abuse= party drug

use= promise for acute depression treatment

Question 20

Ket + PCP MoA (5)

Answer 20

NMDA receptor antagonists:

inc. globally inhib. excitation (anaesthetic)

dec. inhib. NMDARs on interneurons in cortex, inc. excitation

At high concentrations of ketamine and PCP:
* Opioid receptor agonist -sedation
* nAChR antagonist - sedation
* D2 receptor agonist – euphoria, reward
* Monoamine transporter blockade – euphoria, reward