A role for the extended amygdala in the fear-enhancing effects of acute selective serotonin reuptake inhibitor treatment

S Ravinder,E P Bauer,R Brodsky,N S Burghardt,S Chattarji

doi:10.1038/tp.2012.137

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are reported to exacerbate symptoms of anxiety when treatment is initiated. These clinical findings have been extended to animal models wherein SSRIs also potentiate anxiety and fear learning, which depend on the amygdala. Yet, little is known about the role of specific amygdalar circuits in these acute effects of SSRIs. Here, we first confirmed that a single injection of fluoxetine 1 h before auditory fear conditioning potentiated fear memory in rats. To probe the neural substrates underlying this enhancement, we analyzed the expression patterns of the immediate early gene, Arc (activity-regulated cytoskeleton-associated protein). Consistent with previous reports, fear conditioning induced Arc protein expression in the lateral and basal amygdala. However, this was not enhanced further by pre-treatment with fluoxetine. Instead, fluoxetine significantly enhanced expression of Arc in the central amygdala (CeA) and the bed nucleus of the stria terminalis (BNST). Next, we tested whether direct targeted infusions of fluoxetine into the CeA, or BNST, leads to the same fear-potentiating effect. Strikingly, direct infusion of fluoxetine into the BNST, but not the CeA, was sufficient to enhance fear memory. Moreover, this behavioral effect was also accompanied by robust Arc expression in the CeA, similar to the systemic injection. Our results identify a novel role for the BNST in the acute fear-enhancing effects of SSRIs. These findings highlight the need to look beyond the traditional focus on input nuclei of the amygdala and add to accumulating evidence implicating these microcircuits in gating fear and anxiety.

Highlights

We found that fluoxetine did not significantly change freezing during the conditioning session when all tones were included in the analysis (Figure 1b; repeated measures analysis of variance (ANOVA): F(1,25) 1⁄4 2.73, P 1⁄4 0.11)
Consistent with our hypothesis, we found that a single injection of fluoxetine triggered Arc expression in the dorsolateral region of the bed nucleus of the stria terminalis (BNST) (Figures 3c and d; t(2.1) 1⁄4 4.28, Po0.5)
Consistent with earlier reports,[16] we found that a single injection of fluoxetine immediately before conditioning enhances the recall of fear memory a day later

Summary

Introduction

Acute SSRI treatment, before auditory fear conditioning, leads to stronger fear memory,[16] which is consistent with its known anxiogenic effects. The central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST), which together comprise the extended amygdala, serve as the principal output structures of the amygdaloid complex that project to the brainstem and hypothalamus and mediate the expression of fear responses.[23,24] While the CeA mediates expression of conditioned fear responses to brief stimuli, the BNST mediates generalized and sustained fear responses to more diffuse stimulus contingencies.[25,26]

Methods

Results

Conclusion