Neuropeptide Y reduces expression of social fear via simultaneous activation of Y1 and Y2 receptors

Abstract

Background: Neuropeptide Y (NPY) has anxiolytic effects and facilitates extinction of cued and contextual fear in rodents, thereby acting as a resilience factor against exaggerated fear responses after adverse events. We investigated whether NPY influences acquisition, expression and extinction of social fear in a mouse model of social fear conditioning (SFC). Methods: NPY was administered intracerebroventricularly before SFC or before social fear extinction with or without prior administration of Y1 and/or Y2 receptor antagonists. Results: We show that NPY affects SFC-induced social fear in a time point–dependent manner. When administered before SFC, NPY did not affect acquisition, expression and extinction of social fear. However, when administered before social fear extinction, NPY reduced expression of social fear via simultaneous activation of Y1 and Y2 receptors. As such, neither the Y1 receptor antagonist BIBO3304 trifluoroacetate nor the Y2 receptor antagonist BIIE0246 was able to block the effects of NPY completely. However, when administered in combination, they completely blocked the effects of NPY on social fear expression. Conclusions: These findings have important clinical implications, as they suggest that although medication strategies aimed at increasing brain NPY activity are unlikely to prevent the formation of aversive memories after a traumatic social experience, they might improve the recovery from a traumatic social experience by reducing the expression of social fear.

Neuropeptide Y as Alternative Pharmacotherapy for Antidepressant-Resistant Social Fear

“…Interestingly, all control SFC + mice (i.e., water-drinking and vehicle-treated) used in this study failed to show extinction of social fear, i.e., a gradual decrease in social fear as a result of repeated exposure to social stimuli. Gradual social fear extinction has been previously described in untreated and vehicle-treated CD1 mice [22,23,[34][35][36][37][38][39] and is similar to the outcome during exposure therapy in SAD patients [2]. This difference in social fear extinction might arise from potential genetic-related strain differences.…”

“…These strain differences in social behavior were not only observed in SFC + mice but, also, in SFC − mice, i.e., SFC − ASM+/+, ASM+/−, and ASM−/− mice showed lower levels of social investigation during social fear extinction compared with SFC − CD1 mice. SFC − CD1 mice usually spend around 80% of the time investigating the social stimuli [22,23,[34][35][36][37][38][39] and show high levels of aggressive behavior, whereas SFC − C57BL/6 mice used in this study spent around 60% of the time investigating the social stimuli and showed no aggressive behavior.…”

“…Given that i.c.v.-administered NPY reduced SFC-induced social fear in CD1 mice [22], we investigated whether NPY might also reduce the antidepressant-resistant social fear in ASM−/− mice. We demonstrated that acute NPY treatment did not only reduce social fear in ASM+/+ and ASM+/− mice but, also, in ASM−/− mice.…”

“…This indicates that neither the SSRI paroxetine nor the tricyclic antidepressant amitriptyline could reduce social fear in ASM−/− mice. [22], we determined whether NPY could also reduce the antidepressant-resistant social fear in ASM−/− mice. For this, SFC + and SFC − ASM−/−, ASM+/−, and ASM+/+ mice were infused i.c.v.…”

“…These prosocial, anxiolytic, and fear-reducing properties of NPY suggest its potential benefit in disorders associated with social anxiety and fear. Accordingly, we could show that i.c.v.-administered NPY reduces the expression of social fear in an animal model of SAD, namely social fear conditioning (SFC) [22]. 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].…”