Social instigation and aggressive behavior in mice: role of 5-HT1A and 5-HT1B receptors in the prefrontal cortexLigia et al.

Ryan Mullaly

Ventral Orbitofrontal Cortex

Involved in decision-making.

Regulate planning behavior. Reward and

punishment

Ventral Orbitofrontal Cortex

Moderate density of 5-HT receptors in prefrontal cortex. Regulate aggressive and impulsive

behaviorOrbital prefrontal damage linked to

increased impulsive and aggressive behavior. Unaware of implications of actions

Iowa Gambling Task

Simulates real-life decision makingPick cards from good decks or bad

decksHealthy individuals learn and avoid

bad decksPatients with OFC dysfunction never

learn

5-HT

Neurotransmitter involved in regulation of: anger aggression body temp sleep sexuality appetite

Serotonin

5-HT1A and 5-HT1B receptors act as inhibitory autoreceptors. Located on cell bodies and axon terminals, respectively.

Also function as inhibitory heteroreceptors in corticolimbic regions related to modulation of aggression.

Purpose of Study

Assess anti-aggressive effects of 5-HT1A and 5-HT1B agonist receptors in the ventral orbitofrontal cortex of socially provoked male mice.

Specificity confirmed by injection of 5-HT1A and 5-HT1B antagonist receptors.

Methods

Subjects: Adult male mice CF1 (40-50g) Divided into 3 groups:

residents (n=110)intruders (n=110)instigators (n=50)

Methods

All mice maintained on 12:12 h light/dark cycle.

Food/water provided ad libitum.Each resident housed in cage with a

female.Intruders and instigators kept in groups of

ten.Testing took place between hours 9:00-

16:00 of light phase.

Resident-Intruder Confrontation

Resident mice submitted to successive confrontations with intruder.

3x a week, at least 24h intervals.Establish baseline of aggressive

behavior.

Resident-Intruder Confrontation

Each test lasted 5 minutes.Intruder replaced if it attacked

resident.Only kept residents who delivered at

least ten bites.

Social Instigation

Procedure used to increase aggressive behavior.

Exposure of resident that can be seen, heard, and smelled, but is protected by a screen.

Attacks after social instigation generally start with short latency and high frequency.

Social Instigation

Place instigator in resident’s cage in clear perforated cylinder for 5 min.

Remove instigator and wait additional 5 min.

Place intruder in resident cage with no protection for 5 min.

Surgery

Each resident mouse anesthetized and implanted with 26-gauge cannula.

Cannula placed in VO PFC of left hemisphere

Group 1

Injected with 8-OH-DPAT or CP-93,129 .1, .56, 1.0 g/l

Controls injected with saline solution.Injections occurred 15 min before

behavioral test.

Group 2

WAY-100,635 or SB-224,289 injected 30 min before 5-HT1A and 5-HT1B agonists respectively.

Controls received two injections of saline solution.

5 min after last injection, residents exposed to social confrontation.

Behavioral Analysis

Confrontations recorded and observed for aggressive and non-aggressive elements.

Aggressive: sniffing, sideways threat, bite, pursuit,

tail rattleNon-aggressive:

grooming, rearing, walking

Statistical Analysis

Compared baseline aggression with aggression after social instigation.

Dose-effect data from each agonist and antagonist were analyzed using one-way ANOVA.

Results: Control

Aggressive behavior increased with all mice exposed to social instigation

Results: 5-HT1A

Injections of 5-HT1A agonist into VO PFC lowered frequency of attack bites at .56 and 1.0 ug doses.

Injections of antagonist negated these effects

Results: 5-HT1B

Injections of 5-HT1B agonist into VO PFC lowered frequency of attack bites at the lowest dose, .1 ug.

Again, injections of antagonist negated these effects.

Frequency of sideways threat was also reduced with injection of agonist.

Results: Non-aggressive

Motor activity of agonist injected mice was not significantly different from vehicle.

However, significant difference between two types of agonists.

Discussion

Social instigation effective means of increasing aggressiveness in rodents.

5-HT1A and 5-HT1B agonists significantly reduce amount of attacks.

5-HT1B more effective means of reducing aggressiveness than 5-HT1A.

Discussion

Agonists did not reduce tail rattles, sniffing, or in case of 5-HT1A agonist, sideways threat.

Only consummatory effects of aggression were reduced.

Social activity was not affected.Shows a different pattern than other anti-

aggression drugs such as antipsychotics, antidepressants, alcohol...

Discussion

Specificity of 5-HT agonists confirmed with injections of 5-HT antagonists into VO PFC.

Implications

Medial and orbital regions of PFC related to modulation of impulsive aggression.

Damage or dysfunction of PFC leads to several psychiatric conditions. Inability to inhibit aggressive and

impulsive behavior.

Examples

11% reduction in PFC of patients exhibiting impulsive aggression.

Murderers show general reduction in glucose metabolism within PFC.