Abstract
In many social anxiety disorder (SAD) patients, the efficacy of antidepressant therapy is unsatisfactory. Here, we investigated whether mice deficient for the lysosomal glycoprotein acid sphingomyelinase (ASM−/−) represent an appropriate tool to study antidepressant-resistant social fear. We also investigated whether neuropeptide Y (NPY) reduces this antidepressant-resistant social fear in ASM−/− mice, given that NPY reduced social fear in a mouse model of SAD, namely social fear conditioning (SFC). We show that neither chronic paroxetine nor chronic amitriptyline administration via drinking water were successful in reducing SFC-induced social fear in ASM−/− mice, while the same treatment reduced social fear in ASM+/− mice and completely reversed social fear in ASM+/+ mice. This indicates that the antidepressants paroxetine and amitriptyline reduce social fear via the ASM-ceramide system and that ASM−/− mice represent an appropriate tool to study antidepressant-resistant social fear. The intracerebroventricular administration of NPY, on the other hand, reduced social fear in ASM−/− mice, suggesting that NPY might represent an alternative pharmacotherapy for antidepressant-resistant social fear. These results suggest that medication strategies aimed at increasing brain NPY concentrations might improve symptoms of social fear in SAD patients who fail to respond to antidepressant treatments.
Highlights
With a lifetime prevalence of approximately 12% [1], social anxiety disorder (SAD) is the second most common anxiety disorder after specific phobia and is characterized by the persistent fear and avoidance of social situations
Considering that many SAD patients fail to respond to antidepressant therapies, we investigated whether antidepressants fail to reverse symptoms of social fear in acid sphingomyelinase (ASM)−/− mice and whether these mice might represent an appropriate tool for studying antidepressant-resistant social fear
Our study shows for the first time that paroxetine and amitriptyline fail to reduce symptoms of social fear in ASM−/− mice
Summary
With a lifetime prevalence of approximately 12% [1], social anxiety disorder (SAD) is the second most common anxiety disorder after specific phobia and is characterized by the persistent fear and avoidance of social situations. I.c.v.-administered NPY impairs the acquisition and consolidation of cued and contextual fear [18,19,20], impairs the expression of fear memories [21], and facilitates the extinction of cued and contextual fear [20,21] These prosocial, anxiolytic, and fear-reducing properties of NPY suggest its potential benefit in disorders associated with social anxiety and fear. SFC is an animal model that mimics the major behavioral symptoms of SAD, i.e., reduced social investigation and avoidance of conspecifics as indicative of social fear [23,24] Both acute treatment with the benzodiazepine diazepam and chronic treatment with the SSRI paroxetine reversed social fear in socially fear-conditioned (SFC+) mice [23], providing a predictive validity to the SFC model
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