1. Social instigation and aggressive behavior in mice: role of 5-HT 1A and 5- HT 1B receptors in the prefrontal cortex Ligia et al. Ryan Mullaly

2. Ventral Orbitofrontal Cortex zInvolved in decision- making. zRegulate planning behavior. yReward and punishment

3. Ventral Orbitofrontal Cortex zModerate density of 5-HT receptors in prefrontal cortex. yRegulate aggressive and impulsive behavior zOrbital prefrontal damage linked to increased impulsive and aggressive behavior. yUnaware of implications of actions

4. Iowa Gambling Task zSimulates real-life decision making zPick cards from good decks or bad decks zHealthy individuals learn and avoid bad decks zPatients with OFC dysfunction never learn

5. 5-HT zNeurotransmitter involved in regulation of: yanger yaggression ybody temp ysleep ysexuality yappetite

7. Serotonin z5-HT 1A and 5-HT 1B receptors act as inhibitory autoreceptors. Located on cell bodies and axon terminals, respectively. zAlso function as inhibitory heteroreceptors in corticolimbic regions related to modulation of aggression.

9. Purpose of Study zAssess anti-aggressive effects of 5-HT 1A and 5-HT 1B agonist receptors in the ventral orbitofrontal cortex of socially provoked male mice. zSpecificity confirmed by injection of 5- HT 1A and 5-HT 1B antagonist receptors.

10. Methods zSubjects: yAdult male mice CF1 (40-50g) yDivided into 3 groups: xresidents (n=110) xintruders (n=110) xinstigators (n=50)

11. Methods zAll mice maintained on 12:12 h light/dark cycle. zFood/water provided ad libitum. zEach resident housed in cage with a female. zIntruders and instigators kept in groups of ten. zTesting took place between hours 9:00- 16:00 of light phase.

12. Resident-Intruder Confrontation zResident mice submitted to successive confrontations with intruder. z3x a week, at least 24h intervals. zEstablish baseline of aggressive behavior.

13. Resident-Intruder Confrontation zEach test lasted 5 minutes. zIntruder replaced if it attacked resident. zOnly kept residents who delivered at least ten bites.

14. Social Instigation zProcedure used to increase aggressive behavior. zExposure of resident that can be seen, heard, and smelled, but is protected by a screen. zAttacks after social instigation generally start with short latency and high frequency.

15. Social Instigation zPlace instigator in resident’s cage in clear perforated cylinder for 5 min. zRemove instigator and wait additional 5 min. zPlace intruder in resident cage with no protection for 5 min.

16. Surgery zEach resident mouse anesthetized and implanted with 26-gauge cannula. zCannula placed in VO PFC of left hemisphere

18. Group 1 zInjected with 8-OH-DPAT or CP-93,129 .1,.56, 1.0  g/  l zControls injected with saline solution. zInjections occurred 15 min before behavioral test.

19. Group 2 zWAY-100,635 or SB-224,289 injected 30 min before 5-HT 1A and 5-HT 1B agonists respectively. zControls received two injections of saline solution. z5 min after last injection, residents exposed to social confrontation.

20. Behavioral Analysis zConfrontations recorded and observed for aggressive and non-aggressive elements. zAggressive: ysniffing, sideways threat, bite, pursuit, tail rattle zNon-aggressive: ygrooming, rearing, walking

21. Statistical Analysis zCompared baseline aggression with aggression after social instigation. zDose-effect data from each agonist and antagonist were analyzed using one-way ANOVA.

22. Results: Control zAggressive behavior increased with all mice exposed to social instigation

23. Results: 5-HT 1A zInjections of 5-HT 1A agonist into VO PFC lowered frequency of attack bites at.56 and 1.0 ug doses. zInjections of antagonist negated these effects

26. Results: 5-HT 1B zInjections of 5-HT 1B agonist into VO PFC lowered frequency of attack bites at the lowest dose,.1 ug. zAgain, injections of antagonist negated these effects. zFrequency of sideways threat was also reduced with injection of agonist.

31. Results: Non-aggressive zMotor activity of agonist injected mice was not significantly different from vehicle. zHowever, significant difference between two types of agonists.

33. Discussion zSocial instigation effective means of increasing aggressiveness in rodents. z5-HT 1A and 5-HT 1B agonists significantly reduce amount of attacks. z 5-HT 1B more effective means of reducing aggressiveness than 5-HT 1A.

34. Discussion zAgonists did not reduce tail rattles, sniffing, or in case of 5-HT 1A agonist, sideways threat. zOnly consummatory effects of aggression were reduced. zSocial activity was not affected. zShows a different pattern than other anti- aggression drugs such as antipsychotics, antidepressants, alcohol...

35. Discussion zSpecificity of 5-HT agonists confirmed with injections of 5-HT antagonists into VO PFC.

36. Implications zMedial and orbital regions of PFC related to modulation of impulsive aggression. zDamage or dysfunction of PFC leads to several psychiatric conditions. yInability to inhibit aggressive and impulsive behavior.

37. Examples z11% reduction in PFC of patients exhibiting impulsive aggression. zMurderers show general reduction in glucose metabolism within PFC.