Serotonin and Aggression

How many serotonin receptors and transporters are there, and how is serotonin's action terminated?

• At least 14 different 5-HT receptors and 1 transporter (SERT)

• Action is terminated by re-uptake via SERT and degradation by MAO-A

Tryptophan hydroxylase function

Converts tryptophan → 5-HTP

L-AADC function

Converts 5-HTP → 5-HT

Give the signalling mechanism of 5-HT1

Gi, cAMP down

Give the signalling mechanism of 5-HT2

Gq, IP3 + DAG up

Give the signalling mechanism of 5-HT3

Ligand-gated cation channel

Give the signalling mechanism of 5-HT4/6/7

Gs, cAMP up

Where do the most important serotonergic neurons originate?

Dorsal and median raphe nuclei, projecting to forebrain structures involved in higher functions including aggression

What is low serotonin syndrome (low CSF 5-HIAA) associated with?

• Violence

• Impulsivity

• Alcohol abuse

• Suicidality

• Risk-taking

• Antisocial personality

• Intermittent explosive disorder

What is an autoreceptor?

A receptor for 5-HT on the serotonergic neuron itself 5-HT1A on the cell body (reduces firing) and 5-HT1B (and 1D) on the terminal (reduces release)

Which serotonin receptors act as somatodendritic and terminal autoreceptors?

• 5-HT1A on the cell body (reduces firing)

• 5-HT1B (and 1D) on the terminal (reduces release)

Where is SERT found on the neurons?

Both the somadodendritic and synaptic part

What is a heteroreceptor?

• A 5-HT receptor on a non-serotonergic neuron (postsynaptic target, or the terminal of another neuron regulating release of another transmitter)

• 5-HT1B can be both autoreceptor and heteroreceptor

State the 'dogma' about serotonin and aggression

Serotonergic activity is inversely related to aggression (serotonin inhibits aggression)

Which pharmacological profile gives serenic activity in the resident-intruder test?

• Only drugs with 5-HT1A/1B receptor agonistic effects (e.g. eltoprazine, TFMPP, fluprazine) had serenic activity

• 5-HT2 and 5-HT3 antagonists had none

What evidence shows that 5-HT1B receptors mediate anti-aggressive effects in mice?

Selective 5-HT1B agonists (anpirtoline, zolmitriptan) reduce attack bites and sideways threats, and the 5-HT1B antagonist GR127935 antagonises this effect

In the resident-intruder test, how do eltoprazine/TFMPP differ from buspirone, 8-OH-DPAT and fluvoxamine?

• Eltoprazine and TFMPP reduce aggression while social interaction is kept and exploration rises

• Buspirone, 8-OH-DPAT and fluvoxamine also reduce social interaction/exploration or raise inactivity (sedation)

What are serenics, and what is the prototype?

• Anti-aggression medicines (selective anti-aggressive drugs)

• Prototype eltoprazine, a 5-HT1A/1B receptor (partial) agonist; developed 1977-1994, then stopped

What did chronic eltoprazine administration show?

They keep working chronically (no tolerance): aggression stays reduced during 4 days of treatment and returns after the washout day

What did eltoprazine and buspirone do in piglet aggression (social hierarchy)?

Eltoprazine and buspirone are clearly anti-aggressive in piglets, but buspirone also induces sedation

How was it shown that eltoprazine's anti-aggressive effect is post-synaptically mediated?

• 5,7-DHT injected into the raphe nuclei destroys serotonergic cells, leaving only postsynaptic receptors

• Eltoprazine still reduced aggression, so the effect is postsynaptically mediated

How is the lateral hypothalamus linked to aggression in the lecture's model?

Electrical stimulation of the lateral hypothalamus induces attack behaviour; the current threshold (microamps) for aggression, teeth chattering and locomotion is measured

Effect of eltoprazine vs fluvoxamine on electrically induced aggression?

• Eltoprazine selectively raises the aggression threshold without changing teeth-chattering or locomotion

• Fluvoxamine is less selective (also raises the locomotion threshold)

Which knockouts show enhanced aggression?

5-HT1B receptor knockout, MAO-A knockout and Pet1 knockout show enhanced aggression

What are the resident-intruder numbers for the 5-HT1B KO?

In the resident-intruder test the 5-HT1B KO spent about 7% of the time on aggression vs about 1% for WT

List the phenotype of the 5-HT1B receptor knockout mouse

• More aggressive

• Impulsive/disinhibited

• Gregarious

• Higher body weight (not obese)

• More reactive to external stimuli

• Normal sexual behaviour

• Disturbed learning acquisition

• Suggests ADHD / a compulsive phenotype

Human evidence for 5-HT1B in aggression (Jensen et al. 2009)?

Individuals homozygous for the ancestral A-element of the HTR1B mRNA (miR-96 regulated) report more conduct-disorder behaviours than G-carriers, in both males and females

Outline an experiment to test the serenic effect of a drug in an animal model

1. Resident-intruder test (10 min): vehicle, several drug doses, reference serenic (eltoprazine), antagonist alone, antagonist + drug

2. Score aggression plus social interaction, exploration and inactivity

3. Optionally chronic dosing with washout and a 5,7-DHT lesion group with sham control