title: 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.
authors: National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India.
authors: S
authors: S
authors: Ravinder
authors: N S
authors: NS
authors: Burghardt
authors: R
authors: R
authors: Brodsky
authors: E P
authors: EP
authors: Bauer
authors: S
authors: S
authors: Chattarji
mesh_terms: D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism / Q000494:pharmacology*; D001007:Anxiety / Q000378:metabolism; D003213:Conditioning, Psychological / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000187:drug effects* / Q000378:metabolism; D005239:Fear / Q000187:drug effects*; D005473:Fluoxetine / Q000378:metabolism / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D017781:Genes, Immediate-Early / Q000187:drug effects; D007150:Immunohistochemistry; D008297:Male; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012686:Septal Nuclei / Q000187:drug effects* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D003598:Cytoskeletal Proteins; D005473:Fluoxetine; D009419:Nerve Tissue Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C092069:activity regulated cytoskeletal-associated protein