title: In socially isolated mice, the reversal of brain allopregnanolone down-regulation mediates the anti-aggressive action of fluoxetine.
abstract: Social isolation (SI) of male mice lasting >4 weeks is associated with aggression toward intruders and a down-regulation of brain allopregnanolone (Allo) content. SI of female mice fails to down-regulate brain Allo content or to induce aggressiveness. Fluoxetine (Prozac in clinical use) is an S- and R-fluoxetine (FLX) mixture, which in mammals is metabolized into S- and R-norfluoxetine (NFLX). The S isomers of FLX and NFLX are more active than their respective R isomers in normalizing brain Allo down-regulation and in reducing the aggressiveness induced by SI. Thus, FLX stereospecifically reduces brain Allo down-regulation and the aggressiveness induced by SI, whereas serotonin (5-HT) uptake inhibition lacks stereospecificity. The doses of S-FLX and S-NFLX that reduce aggressiveness and Allo brain content down-regulation induced by SI are at least one order of magnitude lower than the doses that block 5-HT reuptake. Doses of imipramine that inhibit 5-HT uptake neither reduce aggressiveness nor normalize brain Allo down-regulation. We conclude that Allo brain content normalization is a better candidate than 5-HT reuptake inhibition to explain the reduction of aggressiveness elicited by S-FLX and S-NFLX.
authors.affiliation: Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois, Chicago, IL 60612, USA.
authors.forename: Graziano
authors.initials: G
authors.lastname: Pinna
authors.forename: Erbo
authors.initials: E
authors.lastname: Dong
authors.forename: Kinzo
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Erminio
authors.initials: E
authors.lastname: Costa
authors.forename: Alessandro
authors.initials: A
authors.lastname: Guidotti
mesh_terms: D000374:Aggression / Q000187:drug effects*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D005473:Fluoxetine / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D011280:Pregnanolone / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D012934:Social Isolation; D013237:Stereoisomerism
chemical_list: D005473:Fluoxetine; D011280:Pregnanolone; D017367:Selective Serotonin Reuptake Inhibitors