Isolation-induced aggression in mice: effects of 5-hydroxytryptamine uptake inhibitors and involvement of postsynaptic 5-HT1A receptors.

The inhibitory potencies of selective serotonin (5-hydroxytryptamine, 5-HT) uptake inhibitors on isolation-induced aggressive behaviour in male mice were studied. Furthermore, the role of postsynaptic 5-HT1A receptors in the mediation of aggressive behaviour was studied. The selective 5-HT uptake inhibitors, sertraline, floxetine, femoxetine and fluvoxamine, showed weak antiaggressive effects, and citalopram and paroxetine were ineffective. This rank of potencies corresponded with neither uptake inhibitory potencies in vitro nor potentiation of 1-5-hydroxytryptophan (1,5-HTP)-induced motor effects in vivo, as citalopram and paroxetine were among the most potent compounds in these tests. A subeffective dose of 1,5-HTP (110 mumol/kg = 25 mg/kg, s.c.) potentiated the antiaggressive effect of citalopram and paroxetine more than 110 and 1600 times, respectively. The effects of sertraline, fluvoxamine, fluoxetine and femoxetine were only potentiated 3, 36, 4 and 16 times, respectively. The 5-HT releasing compound fenfluramine inhibited the aggressive behaviour dose dependently, and depletion of 5-HT by treatment with p-chloro-phenylalanine methyl ester attenuated this effect significantly. p-Chloro-phenylalanine methyl ester was ineffective itself, but potentiated the antiaggressive effect of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamin)tetralin (8-OH-DPAT). The beta-adrenoceptor/5-HT1A receptor antagonist, (-)-penbutolol, reversed the antiaggressive effects of 8-OHDPAT. In conclusion, selective 5-HT uptake inhibitors act in different ways on isolation-induced aggressive behaviour, and postsynaptic 5-HT1A receptors are involved in mediating the aggressive behaviour.