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Social isolation stress-induced aggression in mice: A model to study the pharmacology of neurosteroidogenesis

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 GABAA receptor acting drugs, and a downregulation of brain levels of 3α,5α-tetrahydroprogesterone (allopregnanolone: 3α,5α-THP), a neurosteroid endowed with potent positive allosteric modulatory activity of the action of GABA at various GABAA receptor subtypes. This downregulation of 3α,5α-THP appeared to be associated with the reduction of brain type I 5α-reductase mRNA and protein expression. Systemic administration of the selective serotonin reuptake inhibitor fluoxetine and its metabolite norfluoxetine normalized brain 3α,5α-THP content and reduced responsiveness to GABAA 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 3α,5α-THP brain content, while their ex vivo inhibition of serotonin reuptake occurred at high μmolar doses and lacked stereospecificity. From these results we infer that the brain 3α,5α-THP content physiologically upregulates GABAA receptor responsiveness to GABA and that social isolation induces a reduction of brain 3α,5α-THP content that is probably causally related to the onset of aggression.