MDMA-induced serotonergic neurotoxicity enhances aggressiveness in low- but not high-aggressive rats

Ecstasy or 3,4-methylenedioxymethamphetamine (MDMA) is a frequently (ab)used recreational drug for its acute euphoric effects but on the long-term may cause neurotoxic damage to serotonin (5-hydroxytryptamine; 5-HT) nerve endings in the brain. Since decreased brain 5-HT function has been strongly associated with several impulse control disorders like hostility and violent aggression, ecstasy users might be at risk developing this form of psychopathology. The present study examined the ability of a MDMA administration protocol (3 × 6 mg/kg, with 3 h intervals at 25 ºC ambient temperature), that previously was shown to partially deplete brain serotonin levels, to increase offensive aggressive behavior in male Wild-type Groningen (WTG) rats. This rat strain is known for its broad individual variation in offensive aggression. Resident-intruder aggression was assessed 5 days before and 23 days after MDMA administration. On day 28, MDMA neurotoxicity to 5-HT nerve terminals was assessed by quantification of serotonin reuptake transporter (SERT) immuno-positive axons in defined brain regions. Based on their expressed aggression level in the initial aggression test, rats were divided into low (< 10% aggression), high (> 50% aggression) or medium aggressive (10–50%) groups. The study demonstrated that MDMA treatment increased aggressiveness in only low aggressive rats and not in medium and high aggressive animals. Irrespective of their initial aggressiveness, MDMA significantly reduced the number of SERT-positive axons in all animals. In conclusion, vulnerability for increased aggression long after a single MDMA treatment is dependent on the individual's trait aggressiveness but not on the degree of MDMA-induced serotonergic neurotoxicity.