Targeting PSD95/nNOS by ZL006 alleviates social isolation-induced heightened attack behavior in mice

Abstract

Rationale Deregulated attack behaviors have devastating social consequences; however, satisfactory clinical management for the behavior is still an unmet need so far. Social isolation (SI) has been common during the COVID-19 pandemic and may have detrimental effects on mental health, including eliciting heightened attack behavior. Objectives This study aims to explore whether injection of ZL006 can alleviate SI-induced escalation of attack behavior in mice. Methods Pharmacological tools, biochemical methods, and behavioral tests were used to explore the potential therapeutic effects of ZL006 targeting postsynaptic density 95 (PSD95)/neuronal nitric oxide synthase (nNOS) pathway on escalation of attack behavior induced by SI in mice. Results ZL006 mitigated SI-induced escalated attack behaviors and elevated nitric oxide (NO) level in the cortex of the SI mice. The beneficial effects of ZL006 lasted for at least 72 h after a single injection of ZL006. Potentiation of NO levels by L-arginine blocked the effects of ZL006. Moreover, a sub-effective dose of 7-NI in combination with a sub-effective dose of ZL006 decreased both SI-induced escalated attack behaviors and NO levels in mice subjected to SI. Conclusions Our study highlights the importance of the PSD95/nNOS pathway in mediating SI-induced escalation of attack behavior. ZL006 may be a promising therapeutic strategy for treating aggressive behaviors. Supplementary Information The online version contains supplementary material available at 10.1007/s00213-021-06000-9.

nNOS and Neurological, Neuropsychiatric Disorders: A 20-Year Story

“…It is known that nNOS inhibition can cause aggressive behavior [ 54 ]. A recent study showed that the nNOS-PSD-95 pathway mediates the SI-induced escalation of attack behavior and the dissociation of nNOS-PSD-95 by ZL006 mitigates SI-induced escalated attack behaviors in mice [ 91 ], suggesting a promising therapeutic strategy for treating aggressive behaviors.…”

Animal Models of Aggression

“…In adults, social isolation has been also reported to enhance aggression in several male rodent species such as wild and lab mice, rats, and hamsters (Borland et al 2019;Elliott Albers et al 2006;Koolhaas et al 2013;Miczek et al 2001Miczek et al , 2013Ross et al 2019;Yang et al 2022b;Zelikowsky et al 2018). In adult females, the effects of social isolation on aggressive behavior have been less studied (Oliveira and Bakker 2022).…”

“…Total 2 weeks of social isolation was found to stimulate NO synthesis in the cortex of male mice; this was followed by high levels of aggression. Furthermore, inhibition of NO synthesis using ZL006, an NMDA-R-dependent NO synthesis inhibitor targeting specifically neuronal nitric oxide synthase (nNOS)/PSD95, reduced aggressive behavior in isolated mice (Yang et al 2022b). Conversely, isolated nNOS-KO mice were found to display a higher number of attacks, boxing, and decreased attack latency compared to isolated wild types.…”

Animal Models of Aggression

“…In adults, social isolation has been also reported to enhance aggression in several male rodent species such as wild and lab mice, rats, and hamsters (Borland et al 2019;Elliott Albers et al 2006;Koolhaas et al 2013;Miczek et al 2001Miczek et al , 2013Ross et al 2019;Yang et al 2022b;Zelikowsky et al 2018). In adult females, the effects of social isolation on aggressive behavior have been less studied (Oliveira and Bakker 2022).…”