S-norfluoxetine microinfused into the basolateral amygdala increases allopregnanolone levels and reduces aggression in socially isolated mice

Abstract

A decrease of brain allopregnanolone biosynthesis may play a role in emotion, impulsive behavior, and anxiety spectrum disorders by decreasing GABAergic neurotransmission. In male mice, four weeks of social isolation induces behavioral dysfunctions such as aggression, fear, and anxiety-like behavior associated with a decrease in allopregnanolone biosynthesis in selected corticolimbic structures comprising the basolateral amygdala (BLA), olfactory bulb, hippocampus, and medial prefrontal cortex. Importantly, no decrease in allopregnanolone biosynthesis has been found in the striatum and cerebellum. Given the importance of the amygdaloid complex in emotional behavior, we hypothesized that this brain area may play a pivotal role in decreasing social isolation-induced aggression. Thus, socially isolated mice were directly infused with S-norfluoxetine (S-NFLX) or pregnanolone (an analog of allopregnanolone) into the BLA and striatum. When S-NFLX (2.5, 3.75, and 5 nmol/0.2 μl) or pregnanolone (1.25, 2.5, 3.75, and 5.0 nmol/0.2 μl) is directly infused into the BLA, these agents dose-dependently reduced aggression (S-NFLX up to 93% and pregnanolone up to 96%) of a socially isolated mouse to a same-sex intruder. However, S-NFLX (3.75 and 5 nmol) infused directly into the striatum failed to alter aggression. Allopregnanolone content in the BLA after S-NFLX (3.75 nmol) infusion was increased by 3-fold and in the hippocampus, by 80%. Allopregnanolone levels did not change in the olfactory bulb or in the frontal cortex of the same mice. S-NFLX (3.75 nmol) infused into the striatum failed to increase the levels of allopregnanolone. These results suggest that S-NFLX, acting as a selective brain steroidogenic stimulant (SBSS), increases corticolimbic allopregnanolone levels and regulates aggression, which underscores the pivotal role of the BLA and hippocampus in the regulation of aggressiveness in socially isolated mice. This article is part of a Special Issue entitled ‘Trends in Neuropharmacology: In Memory of Erminio Costa’.