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.
Highlights
Selective serotonin reuptake inhibitors (SSRIs) are used routinely in the treatment of depression and a wide range of anxiety disorders (Sheehan et al, 1993; van der Kolk et al, 1994; Stokes and Holtz, 1997; Kent et al, 1998; Bezchlibnyk-Butler et al, 2000; Bondareff et al, 2000; Stahl, 2000; Gorman, 2003)
These results show that the acute anxiogenic effects of fluoxetine are not accompanied by an increase in spine density of the primary apical dendrites on basolateral amygdala (BLA) principal neurons
Despite growing evidence pointing to a pivotal role for the amygdala in the debilitating emotional symptoms of depression and anxiety, few studies have addressed the role of cells and circuits in the amygdala in mediating the behavioral effects of antidepressants
Summary
Selective serotonin reuptake inhibitors (SSRIs) are used routinely in the treatment of depression and a wide range of anxiety disorders (Sheehan et al, 1993; van der Kolk et al, 1994; Stokes and Holtz, 1997; Kent et al, 1998; Bezchlibnyk-Butler et al, 2000; Bondareff et al, 2000; Stahl, 2000; Gorman, 2003). The acute anxiogenic effect of SSRIs has been demonstrated in numerous rodent models of anxiety-like behavior (Bodnoff et al, 1989; Griebel et al, 1994; Sanchez and Meier, 1997; Dekeyne et al, 2000; Kurt et al, 2000; Silva and Brandao, 2000; Bagdy et al., 2001; Belzung et al, 2001; Koks et al, 2001; Salchner and Singewald, 2002) Another promising lead comes from LeDoux and colleagues who have shown that the same acute SSRI treatment that increases anxiety-like behavior enhances the acquisition of fear memory in an auditory fear conditioning task (Burghardt et al, 2004, 2007). Despite the pivotal role played by the amygdala in fear, anxiety, and depression, little is known about
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