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

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.

Chronic fluoxetine dissociates contextual from auditory fear memory

“…While the serotonergic modulation of fear memory has been extensively studied [27, 32–37], these experiments are the first to examine the effects of chronic, preconditioning fluoxetine on both the contextual and auditory fear memory of mice. Using two differing experimental paradigms, the fluoxetine treatment of adult mice impaired their contextual fear memory, but spared auditory fear memory.…”

“…In contrast, auditory freezing tends to be increased or unaltered by SSRI treatment [27, 34, 37, 38]. In these previous studies, decreased contextual freezing was attributed to an anxiolytic effect for the medication [33–36].…”

The Human BNST: Functional Role in Anxiety and Addiction

“…Benzodiazpine administration also reduced CRF-enhanced startle, suggesting that the effect generalizes to other paradigms that measure BNST-mediated responses (Swerdlow et al, 1986). Another study showed that an acute injection of fluoxetine into the BNST of fear conditioned rodents enhanced fear acquisition and this effect was not seen for injections into the amygdala (Ravinder et al, 2013). Together, these findings suggest that the BNST and BNST-mediated behaviors respond uniquely to pharmacological agents, although much remains to be learned about the exact nature of these relationships and the implications for clinical practice.…”

Fear Memory

“…Ravinder et al (522) confirmed the fear-enhancing effect of SSRIs, studying the possible role of the Arc gene in the CE in this, and examine the involvement of the extended amygdala, not just the amygdala in SSRI effects. They found that the also prototypical SSRI fluoxetine increases Arc in the CE, and its administration into the bed BNST, a part of the "extended amygdala" (13), produces a fear potentiation similar to that induced by systemic administration of the drug, also accompanied by an Arc increase in the CE.…”