Endocannabinoids

Question 1

What is the Endocannabinoid System (ECS)?

Answer 1

The endocannabinoid system is a neuromodulatory system that:
- Fine-tunes neurotransmission
- Maintains homeostasis
- Regulates mood, memory, reward, pain, appetite, and stress
Exam definition:
- A retrograde signalling system using lipid-derived neurotransmitters acting mainly via CB1 and CB2 G-protein coupled receptors

Question 2

What are the three core components of the ECS?

Answer 2

The ECS consists of:
- Endocannabinoids (ligands)
- Cannabinoid receptors (CB1 and CB2)
- Enzymes for synthesis and breakdown

Question 3

What are endocannabinoids?

Answer 3

Endocannabinoids are:
- Lipid-derived (fat-based)
- Not stored in vesicles
- Synthesised on demand from membrane phospholipids

Question 4

What are the two main endocannabinoids (exam list)?

Answer 4

The two main endocannabinoids are:
- Anandamide (AEA) – partial CB1 agonist
- 2-arachidonoylglycerol (2-AG) – full CB1 agonist

Question 5

How are endocannabinoids synthesised?

Answer 5

Endocannabinoids are synthesised postsynaptically:
- Postsynaptic neuron activation
- Intracellular Ca²⁺ increases
- Membrane phospholipids converted into anandamide or 2-AG
Exam trap:
- Not pre-stored
- Not released from vesicles

Question 6

What is retrograde transmission?

Answer 6

Retrograde transmission means:
- Signalling travels from postsynaptic → presynaptic neuron
- Opposite of classical neurotransmission
Effect:
- Reduced presynaptic neurotransmitter release

Question 7

Where are CB1 receptors located?

Answer 7

CB1 receptors are:
- The most abundant GPCR in the brain
Main locations:
- Cerebral cortex
- Hippocampus
- Basal ganglia
- Cerebellum
- Limbic system
Exam pearl:
- Sparse in brainstem (minimal respiratory depression)

Question 8

Where are CB2 receptors located?

Answer 8

CB2 receptors are mainly located in:
- Immune cells
- Microglia
- Spleen
- Tonsils
- Peripheral tissues
Function:
- Immunomodulation
- Anti-inflammatory effects

Question 9

What type of receptors are CB1 and CB2?

Answer 9

CB1 and CB2 receptors are:
- G-protein coupled receptors
- Gi/o-coupled
Effects:
- ↓ adenylyl cyclase
- ↓ cAMP
- Inhibitory signalling

Question 10

How does CB1 activation reduce neurotransmitter release?

Answer 10

CB1 activation causes presynaptic inhibition:
- Endocannabinoid binds CB1
- Gi/o protein activated
- Voltage-gated Ca²⁺ channels close
- ↑ K⁺ efflux
- ↓ Vesicle fusion
Result:
- Reduced neurotransmitter release

Question 11

Which neurotransmitters are inhibited by CB1 activation?

Answer 11

CB1 activation reduces release of:
- Glutamate
- GABA
- Dopamine
- Noradrenaline

Question 12

How are endocannabinoids broken down?

Answer 12

Endocannabinoids are rapidly degraded:
- Anandamide → FAAH
- 2-AG → MAGL
Exam trap:
- No reuptake pumps
- Intracellular breakdown

Question 13

What are the main functions of the ECS?

Answer 13

Main ECS functions:
- Mood regulation
- Anxiety modulation
- Fear extinction
- Reward & addiction
- Stress response
- Appetite & metabolism
- Pain modulation
- Immune regulation

Question 14

How does THC interact with the ECS?

Answer 14

THC:
- Is a partial CB1 agonist
- Mimics anandamide
Effects:
- ↑ Dopamine
- Altered perception
- Memory impairment
- Anxiety & psychosis risk

Question 15

What are key exam traps about the ECS?

Answer 15

Exam traps:
- Endocannabinoids are not classical neurotransmitters
- Not stored in vesicles
- Not released presynaptically
- CB1 activation inhibits neurons

Question 16

What are the five key exam take-home points for the ECS?

Answer 16

Key exam points:
- Lipid-derived, on-demand
- Retrograde signalling
- CB1 = brain
- CB2 = immune
- Gi-coupled inhibitory system“Why is the endocannabinoid system (ECS) relevant to psychosis?

Question 17

How does the ECS normally regulate dopamine transmission?

Answer 17

Normal ECS function acts as a brake system:
- Dopamine neurons fire in the mesolimbic pathway
- Postsynaptic neurons release endocannabinoids
- CB1 receptors on presynaptic terminals are activated
- Glutamate input decreases
Result:
- Dopamine firing is limited

Question 18

What happens to dopamine signalling when THC disrupts the ECS?

Answer 18

THC disruption causes:
- Excess CB1 activation
- Disinhibition of dopamine neurons
- Increased mesolimbic dopamine
Result:
- Psychotic symptoms
Exam phrase:
- Cannabis increases psychosis risk via dysregulation of endocannabinoid modulation of dopamine

Question 19

Which individuals are most vulnerable to ECS-related psychosis?

Answer 19

High-risk groups include:
- Adolescents
- High-potency cannabis users
- Individuals with genetic vulnerability (e.g. COMT variants)
- Early onset cannabis use (<15 years)
Exam trap:
- Not all cannabis users develop psychosis

Question 20

How is the ECS linked to schizophrenia pathophysiology?

Answer 20

Findings in schizophrenia include:
- Increased anandamide levels in CSF
- Altered CB1 receptor expression
- Interaction with the glutamate hypothesis
Interpretation:
- ECS changes may be compensatory, not purely causative

Question 21

What is the normal role of the ECS in anxiety regulation?

Answer 21

The ECS normally has an anxiolytic role:
- Dampens excessive fear responses
- Regulates stress reactivity
Key brain regions:
- Amygdala
- Prefrontal cortex
- Hippocampus

Question 22

How does CB1 activation reduce anxiety mechanistically?

Answer 22

CB1 activation reduces anxiety by:
- Reducing glutamate release in fear circuits
- Suppressing HPA axis activation
- Lowering cortisol release
Concept:
- ECS acts as a volume control on fear

Question 23

Why can cannabis sometimes cause anxiety or panic?

Answer 23

Cannabis effects are dose-dependent:
- Low CB1 activation → anxiolytic
- High CB1 activation (THC) → anxiety, panic, paranoia
Exam buzzword:
- Biphasic effect of cannabinoids

Question 24

Which anxiety disorders are linked to ECS dysfunction?

Answer 24

ECS dysfunction is linked to:
- Generalised anxiety disorder
- Panic disorder
- PTSD
High-yield concept:
- ECS is crucial for fear extinction

Question 25

**How does the ECS regulate reward and addiction?**

Answer 25

The ECS interacts with: - **Dopamine reward pathways** - The **opioid system** - **Habit circuits** in the **basal ganglia** Key pathway: - **Mesolimbic dopamine pathway** (VTA → nucleus accumbens)

Question 26

**What happens to dopamine neurons when CB1 receptors are activated?**

Answer 26

CB1 activation: - **Inhibits GABA interneurons** - Causes **disinhibition of dopamine neurons** - Leads to **increased dopamine release** Key exam phrase: - CB1 activation **indirectly increases dopamine firing**

Question 27

**How does the ECS contribute to substance addiction?**

Answer 27

ECS involvement includes: - **Reward amplification** - **Craving** - **Relapse vulnerability** Concept: - The ECS acts as a **final common modulator of reward**

Question 28

**Which substances interact with the ECS (exam list)?**

Answer 28

Substances interacting with the ECS: - **Cannabis** - **Alcohol** - **Opioids** - **Nicotine** - **Psychostimulants**

Question 29

**How does the ECS contribute to relapse in addiction?**

Answer 29

Relapse mechanisms include: - **Stress-induced ECS activation** - **Cue-induced craving** Result: - Increased risk of **relapse**

Question 30

**What are key exam traps about the ECS in psychiatry?**

Answer 30

Exam traps: - ECS is **not purely excitatory** - ECS is **not a classical neurotransmitter system** - THC is a **partial agonist** that is **long-acting** - High CB1 activation can worsen **anxiety and psychosis**

Question 31

**What are the five key exam take-home points for ECS in psychiatry?**

Answer 31

Key exam points: - ECS **modulates dopamine, glutamate, and GABA** - THC increases psychosis risk via **CB1–dopamine effects** - ECS is critical for **fear extinction** - Cannabinoids show **biphasic anxiety effects** - ECS is central to **reward, craving, and relapse**