Chronic treatment with eltoprazine does not lead to tolerance in its anti-aggressive action, in contrast to haloperidol.

The behavioral effects of eltoprazine and haloperidol during a 4 week treatment period were studied in the resident-intruder model of aggression in male rats. Eltoprazine, a serotonergic (5-HT1A/1B) agonist with specific anti-aggressive actions in animals, was compared to haloperidol, a neuroleptic often used to control behavioral disorders. Eltoprazine (1 or 3 mg/kg p.o.) and haloperidol (2 mg/kg p.o.) were given 60 min before a 10 min aggression test. Acutely, eltoprazine reduced aggression, without adversely affecting other behaviors. Eltoprazine (1 or 3 mg/kg p.o.) was subsequently given daily for 4 weeks and aggression tests were performed each week. The anti-aggressive effects of eltoprazine remained stable over the period of 4 weeks whereas exploration was increased. After a wash-out period of 1 week aggression had returned to baseline levels. Acutely given, haloperidol (2 mg/kg p.o.) completely reduced aggression concomitant with massive sedation. Significant tolerance developed to the sedatory actions of haloperidol over the 4 week treatment period. Aggression returned slowly, but remained below baseline values. One week after wash-out a new challenge with haloperidol (2 mg/kg p.o.) revealed significant tolerance. After 2 weeks wash-out aggression had returned to baseline. The data demonstrate persistent and specific anti-aggressive effects after eltoprazine showing no tolerance. In contrast, haloperidol showed tolerance and rebound effects for aggression. The development of tolerance after haloperidol has a different course for sedation than for the anti-aggressive action.