Regional Specific Modulation of Stress-Induced Neuronal Activation Associated with the PSD95/NOS Interaction Inhibitor ZL006 in the Wistar Kyoto Rat

Abstract

BackgroundTo determine brain areas involved in the antidepressant-related behavioral effects of the selective neuronal nitric oxide synthase inhibitor 1-(2-Trifluoro-methyl-phenyl) imidazole (TRIM) and experimental test compound 4-((3,5-dichloro-2-hydroxybenzyl)amino)-2-hydroxybenzoic acid (ZL006), an inhibitor of the PSD of 95 kDa/neuronal nitric oxide synthase interaction in the N-methyl-D-aspartic acid receptor signalling pathway, regional specific expression of the neuronal activation marker c-FOS was assessed following exposure to the forced swimming test in the Wistar Kyoto rat.MethodsWistar Kyoto rats were subjected to a 15-minute swim pretest (pre-forced swimming test) period on day 1. At 24, 5, and 1 hour prior to the 5-minute test, which took place 24 hours following the pre-forced swimming test, animals were treated with TRIM (50 mg/kg; i.p.), ZL006 (10 mg/kg; i.p.), or saline vehicle (1 mL/kg i.p). Behavior was recorded during both pretest and test periods.ResultsBoth TRIM and ZL006 decreased immobility time in Wistar Kyoto rats in the forced swimming test. Exposure to the forced swimming test increased c-FOS immunoreactivity in the lateral septum, paraventricular nucleus of the hypothalamus, periaqueductal grey, dentate gyrus, and ventral CA1 of the hippocampus compared with non-forced swimming test-exposed controls. Forced swimming test-induced c-FOS immunoreactivity was further increased in the lateral septum, periaqueductal gray, and paraventricular nucleus of the hypothalamus following treatment with TRIM or ZL006. By contrast, forced swimming test-induced c-FOS immunoreactivity was reduced in dorsal dentate gyrus and ventral CA1 following treatment with TRIM or ZL006. Exposure to the forced swimming test resulted in an increase in NADPH diaphorase staining in the paraventricular nucleus of the hypothalamus. This forced swimming test-induced increase was attenuated following treatment with ZL006 and points to the paraventricular nucleus as a brain region where ZL006 acts to attenuate forced swimming test-induced neuronal nitric oxide synthase activity while concomitantly regulating region specific neuronal activation associated with an antidepressant-related response.ConclusionsThis study identified a pattern of enhanced and reduced forced swimming test-related c-FOS immunoreactivity indicative of a regulated network where inhibition of nitric oxide coupled to the N-methyl-D-aspartic acid receptor leads to activation of the lateral septum, periaqueductal gray, and paraventricular nucleus of the hypothalamus with concomitant inhibition of the hippocampus.

Validation of Wistar-Kyoto rats kept in solitary housing as an animal model for depression using voxel-based morphometry

“…Brain atrophy observed in the right lateral septum neighbouring the fimbria remained when the stricter threshold was applied, and a negative correlation with escape behaviour was detected. Although the septal area is rarely described in clinical depression studies using MRI, previous animal studies reported that the septal nuclei are involved in stress responses 52 . In addition, lesion studies of the septum reported aggressive behaviours 53 , 54 .…”

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

“…However, inhibitors that directly target NMDAR and NOS have a number of side effects, which means that there is an urgent need for alternative approaches to inhibit NMDAR-dependent production of NO. Considering that PSD95 tethers nNOS to NMDAR and that selective disruption of PSD95/nNOS spares memory and motor function (Smith et al 2016 ), we hypothesized that ZL006, a validated pharmacological tool in numerous rodent models of neurological disease (Carey et al 2017 ; Qu et al 2020 ; Sherwin et al 2017 ), would suppress the attack behaviors induced by SI. Given previous research demonstrating that ZL006 has a limited ability to penetrate the blood–brain barrier (Wang et al 2015 a), we also administered ZL006 via the i.c.v route to test the central action of the drug.…”

Validation of the Wistar-kyoto Rat Kept in Solitary Housing as an Animal Model for Endogenous Depression Using Voxel-based Morphometry

“…Brain atrophy observed in the right lateral septum neighbouring the mbria remained when the stricter threshold was applied, and a negative correlation with escape behaviour was detected. Although the septal area is rarely described in clinical depression studies using MRI, previous animal studies reported that the septal nuclei are involved in stress responses 49 . In addition, lesion studies of the septum reported aggressive behaviours 50,51 .…”