11.2. Psychedelics: Neurobiology & serotonin transmission

Psychedelics: Mechanism of action - 5-HT42

- Psychedelics interact with the serotonin (5-HT) system

- Serotonin 5-HT2A receptor particularly important for hallucinations.

What receptor complex is involved in hallucinations caused by psychedelics?

5-HT2A and mGluR2

What type of receptor is 5-HT2A?

Gq-coupled serotonin receptor

What type of receptor is mGluR2?

Gi-coupled glutamate receptor

Monoamines: Catecholamines

Dopamine (DA)

Norepinephrine (NE)

Epinephrine (Epi)

Monoamines: Indolamines

Serotonin (5-HT)

Serotonin: Synthesis

Serotonin (5-hydroxytryptamine, or 5-HT) is synthesized fromamino acid precursor tryptophan

Tryptophan is converted to 5-HTP by enzyme tryptophanhydroxylase (TPH).

TPH is the rate-limiting step.

5-HTP is then converted to 5-HT (serotonin) by AADC

What is the role of VMAT2 in serotonin transmission?

Packaged into vesicles by VMAT2

How is serotonin primarily inactivated?

Via rapid reuptake by the serotonin transporter (SERT)

What is the secondary mechanism of serotonin inactivation?

Metabolism via monoamine oxidase (MAO)

How many 5-HT receptor subtypes are there?

Fourteen

Which 5-HT receptor subtype is not metabotropic?

5-HT3

What type of receptors are 5-HT autoreceptors?

Gi

Which 5-HT receptor subtypes are found at axon terminals?

5-HT1B or 5-HT1D

Which 5-HT receptor subtype is found in the soma and dendrites?

5-HT1A

What type of receptor is the 5-HT2A receptor?

Gq-coupled

Where is the 5-HT2A receptor expressed?

Cerebral cortex, striatum, and other brain areas

What type of substances can act as agonists for the 5-HT2A receptor?

Some are hallucinogenic

What type of substances can act as antagonists for the 5-HT2A receptor?

Some are antipsychotic

Where are most 5-HT cell bodies (nuclei) located?

Along the midline of the brainstem in the raphe nuclei.

What is the distribution of 5-HT projections in the brain?

Widespread innervation throughout the brain.

Drugs that inhibit SERT

- More 5-HT available in synapse

- Selective serotonin reuptake inhibitors (SSRIs)

- Cocaine

Drugs that inhibit 5-HT synthesis:

Less 5-HT overall

Drugs that are 5-HT neurotoxins:

Destroy 5-HT axons and terminals

Functional roles

CNS: Mood (depression, anxiety), hunger, pain sensitivity, learning and memory, addiction

Functional roles: Anxiety

5-HT1A agonists reduce anxiety

Functional roles: Depression

SSRIs used to treat depression and mood regulation in humans.

LSD and other psychedelics are agonists at postsynaptic 5-HT2A receptors

Evidence: 1. Affinity for 5-HT2A receptors

2. Effects blocked by 5-HT2A antagonists/knockout

3. Expression of 5-HT2A and mechanisms in cortex

4. Effects of other 5-HT2A agonists

5. Interactions with 5-HT2A and mGluR2 receptors

1. Affinity for 5-HT receptors

- Common affinity for 5HT2A and 5HT2C receptor among hallucinogens.

- Significant correlation between 5HT2A binding affinity and psychedelic effects

2. Effects of 5-HT2A antagonists

- 5-HT2A antagonists block subjective effects of hallucinogens in humans

- 5-HT2A antagonists dose-dependently reduce responding at hallucinogen (LSD) lever in animals

2. Effects of 5-HT2A knockout

- Drugs that cause hallucinations in humans cause head twitch in mice (don't know if they have hallucinations).

- Hallucinogen-evoked behaviors (head twitch) are missing in 5-HT2A knockout mice.

- Selective restoration of 5-HT2A receptors in cortex only

3. 5-HT2A receptors expressed in cerebral cortex

layer V (output layer) of cerebral cortex.

3. Psychedelics increase excitation in cortex

5-HT2A receptor stimulation enhances glutamate-mediated excitation of neurons in prefrontal cortex (PFC). This interferes with gating of sensory information from other parts of cortex

How do psychedelics affect cortical organization?

Psychedelics reduce cortical organization/coupling.

What is the disorganizing influence of psychedelics on the cortex?

They allow greater flexibility.

What effect do psychedelics have on the default mode network (DMN)?

Psychedelics reduce activity in the default mode network (DMN).

What effect does LSD have on cerebral blood flow (CBF) in the visual cortex?

LSD causes increased cerebral blood flow (CBF) to the visual cortex.

What is one effect of LSD on cortical organization?

LSD decreases organization of the cortex.

4. Effects of 5-HT2A agonists

not all 5-HT2A agonists are hallucinogenic

What type of signaling do all 5-HT2A agonists involve?

Gq signaling

What type of signaling do hallucinogenic 5-HT2A agonists involve?

Gq and Gi signaling

What two receptors form the receptor complex involving 5-HT2A and mGluR2?

5-HT2A (Gq) and mGluR2 (glutamate receptor, Gi)

Psychedelics: Serotonin mechanism of action

- Psychedelics have high affinity for postsynaptic 5-HT2A receptors

- Hallucinogenic effects blocked

- 5-HT2A receptors are highly expressed in cerebral cortex, and psychedelics cause increased excitability and disorganization in cortex

- Only some are hallucinogenic

- Psychedelics interact with receptor complex formed by 5-HT2A (Gq) and mGluR2 (Gi)