Cellular Correlates of Enhanced Anxiety Caused by Acute Treatment with the Selective Serotonin Reuptake Inhibitor Fluoxetine in Rats

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are used extensively in the treatment of depression and anxiety disorders. The therapeutic benefits of SSRIs typically require several weeks of continuous treatment. Intriguingly, according to clinical reports, symptoms of anxiety may actually increase during the early stages of treatment although more prolonged treatment alleviates affective symptoms. Consistent with earlier studies that have used animal models to capture this paradoxical effect of SSRIs, we find that rats exhibit enhanced anxiety-like behavior on the elevated plus-maze 1 h after a single injection of the SSRI fluoxetine. Next we investigated the potential neural substrates underlying the acute anxiogenic effects by analyzing the morphological and physiological impact of acute fluoxetine treatment on principal neurons of the basolateral amygdala (BLA), a brain area that plays a pivotal role in fear and anxiety. Although earlier studies have shown that behavioral or genetic perturbations that are anxiogenic for rodents also increase dendritic spine density in the BLA, we find that a single injection of fluoxetine does not cause spinogenesis on proximal apical dendritic segments on BLA principal neurons an hour later. However, at the same time point when a single dose of fluoxetine caused enhanced anxiety, it also enhanced action potential firing in BLA neurons in ex vivo slices. Consistent with this finding, in vitro bath application of fluoxetine caused higher spiking frequency and this increase in excitability was correlated with an increase in the input resistance of these neurons. Our results suggest that enhanced excitability of amygdala neurons may contribute to the increase in anxiety-like behavior observed following acute fluoxetine treatment.

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

“…11, 12, 13, 14, 15 The amygdala is known to be an important component of anxiety circuits in the brain 50, 51 and aberrant amygdala activity is associated with affective symptoms of numerous psychiatric disorders. 52, 53, 54, 55 Furthermore, there are reports that acute administration of SSRIs increase amygdala activity 56, 57 and fear-potentiated startle responses in healthy humans.…”

“…1, 2, 3, 4 Although long-term treatment with SSRIs yields therapeutic benefits, they exacerbate symptoms of anxiety when treatment is initiated, potentially leading to an increased risk of suicidal ideation. 5, 6, 7, 8, 9, 10 Although the acute anxiogenic effects of SSRIs have been demonstrated in numerous rodent models of anxiety-like behavior, 11, 12, 13, 14, 15 the cellular substrates of these acute effects are largely unknown.…”

Sex differences and estrous cycle in female rats interact with the effects of fluoxetine treatment on fear extinction

“…In auditory fear conditioning, acute administration of the SSRI citalopram prior to and after fear conditioning increases the expression of fear responses and the formation of fear memory [23, 31] possibly via enhance activation of 5-HT 2c receptors [23, 32]. Ravinder et al (2011) showed that acute fluoxetine treatment enhanced anxiety-like behavior in elevated plus maze possibly via enhancing excitability of BLA neurons [33]. Regarding anxiolytic effects of SSRIs, recent rodents studies showed that chronic administration of SSRIs decreases fear responses during different experimental models of anxiety.…”

Pharmacology of serotonin and female sexual behavior

“…Since acute fluoxetine has anxiogenic properties (Birkett et al, 2011; Ravinder et al, 2012; Robert et al, 2011) and progesterone is recognized as a potent anxiolytic (Bitran et al, 1993; Frye, 2007; Picazo and Fernandez-Guasti, 1995), these findings suggest that stress could amplify the effects of fluoxetine on lordosis behavior and that progesterone may reduce this effect. An additional connection between a potential protective effect of progesterone against the lordosis-inhibiting effect of fluoxetine has been provided by Frye and colleagues (Frye, 2007; Frye et al, 1998; Frye and Rhodes, 2010) who reported that the progesterone metabolite, allopregnanolone (3α-hydroxy-5β-pregnan-20-one; 3α,5β-THP), whether delivered systemically or intracranially into the ventral tegmental area, attenuated the effects of systemic treatment with fluoxetine.…”