Long-term social isolation of laboratory animals is a model to study the behavioral and neurochemical consequences of the absence of social interaction in rodents. Many of the symptoms induced by isolation resemble depression and anxiety disorder symptomatology. Our studies have revealed that male mice socially isolated for more than 4 weeks, exhibit increased aggressiveness, a reduced responsiveness to GABA(A) receptor acting drugs, and a downregulation of brain levels of 3alpha,5alpha-tetrahydroprogesterone (allopregnanolone: 3alpha,5alpha-THP), a neurosteroid endowed with potent positive allosteric modulatory activity of the action of GABA at various GABA(A) receptor subtypes. This downregulation of 3alpha,5alpha-THP appeared to be associated with the reduction of brain type I 5alpha-reductase mRNA and protein expression. Systemic administration of the selective serotonin reuptake inhibitor fluoxetine and its metabolite norfluoxetine normalized brain 3alpha,5alpha-THP content and reduced responsiveness to GABA(A) mimetic drugs in a stereospecific manner. These drugs in nanomolar doses also reduced social isolation-induced aggressiveness with the same stereospecificity as detected in their action on 3alpha,5alpha-THP brain content, while their ex vivo inhibition of serotonin reuptake occurred at high micromolar doses and lacked stereospecificity. From these results we infer that the brain 3alpha,5alpha-THP content physiologically upregulates GABA(A) receptor responsiveness to GABA and that social isolation induces a reduction of brain 3alpha,5alpha-THP content that is probably causally related to the onset of aggression.