Oxytocin Prevents the Development of 3-NP-Induced Anxiety and Depression in Male and Female Rats: Possible Interaction of OXTR and mGluR2

Abstract

Huntington disease (HD) is a progressive neurological disorder with dominant motor symptoms. It also has psychiatric manifestations, like anxiety and depression, that can emerge themselves before motor symptoms and impose a major burden on patients. Oxytocin (OXT) is a newly emerged treatment for disorders like autism and schizophrenia and recently is using to alleviate depression and anxiety. In the current study, we investigated the behavioral and molecular effects of OXT on the development of anxiety and depression in 3-nitropropionic acid (3-NP)-induced model of HD. Anxiety- and depression-like behaviors as well as the levels of oxytocin receptor (OXTR), metabotropic glutamate receptor (mGluR) 2, mGluR5, and glutathione (GSH) were measured in striatum, hippocampus, prefrontal cortex, and amygdala. Also, we questioned if sex had any modulatory effect. We found that 3-NP increased anxiety and depression compared to controls. It also reduced the levels of OXTR and mGluR2, increased mGluR5, and reduced GSH in studied brain regions. Pretreatment with OXT before the injection of 3-NP ameliorated anxiety and depression. Additionally, it protected the brain from developing low levels of OXTR, mGluR2, and GSH and high levels of mGluR5 in studied regions. The protective effects of OXT were similar between male and female animals. These data suggest that OXTR, mGluR2, mGluR5, and GSH may contribute to psychiatric manifestations of HD. In addition, pretreatment with OXT could prevent the mood changes in male and female rats.

Keywords: 3-NP; Anxiety; Depression; Huntington disease; Oxytocin.

Fig. 1

Effects of OXT injection in male and female rats on 3-NP-induced behavioral impairments in OFT. In the Open field test, OXT or the same volume of saline (control group) was injected in rats one day prior to 3-NP administration. a Distance moved in male and d female, b the center zone entries in male and e female, and c the time spent in the center zone in male and f female rats were evaluated. Data are presented as mean ± SEM. (n = 8/group). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 compared with their respective Control; #p < 0.05, ##p < 0.01, ###p < 0.001 compared between the 3-NP and 3-NP + OXT groups using one-way analysis of variance (ANOVA) followed by Tukey's multiple comparison test

Fig. 2

Effects of OXT injection in male and female rats on 3-NP-induced behavioral impairments in EPM. In the elevated plus maze test, OXT or the same volume of saline (Control group) was injected in rats one day before to 3-NP administration. a The time spent in the open arm in male and d female, b the time spent in the closed arm in male and e female, and c the time spent in center zone compartment in male and f female rats were evaluated. Data are presented as mean ± SEM. (n = 8/group). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 compared with their respective Control; ###p < 0.001, ####p < 0.0001 compared between the 3-NP and 3-NP + OXT groups using one -way analysis of variance (ANOVA) followed by Tukey's multiple comparison test

Fig. 3

Effects of OXT injection on 3-NP-induced depressive-like symptoms in male and female rats. In the forced swim test, OXT or the same volume of saline (Control group) was injected in rats one day before to 3-NP administration. a The struggling time in male and e female, b swimming time in male and f female, c the immobility time in male and g female and d the first immobilization time in male and h female rats were evaluated. Data are presented as mean ± SEM. (n = 8/group). *p < 0.05, ***p < 0.001, ****p < 0.0001 compared with their respective Control; #p < 0.05, ##p < 0.01, ###p < 0.001, ####p < 0.0001 compared between the 3-NP and 3-NP + OXT groups using one-way analysis of variance (ANOVA) followed by Tukey's multiple comparison test

Fig. 4

Effect of OXT injection on OXTR, mGluR2 and mGluR5 level in different brain regions of 3-NP administrated male rats. a Representative western blot results of OXTR, mGluR2 and mGluR5 expression level in striatum, hippocampus, prefrontal cortex and amygdala along with their corresponding quantification levels of b OXTR, c mGluR2, and d mGluR5. Data are presented as mean ± SEM. (n = 6 /group). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 compared with their respective Control; #p < 0.05, ##p < 0.01, ###p < 0.001, ####p < 0.0001 compared between the 3-NP and 3-NP + OXT groups using one-way analysis of variance (ANOVA) followed by Tukey's multiple comparison test. β-actin is the internal standard

Fig. 5

Effect of OXT injection on OXTR, mGluR2 and mGluR5 level in different brain regions of 3-NP administrated female rats. a Representative western blot results of OXTR, mGluR2 and mGluR5 expression level in striatum, hippocampus, prefrontal cortex and amygdala along with their corresponding quantification levels of b OXTR, c mGluR2, and d mGluR5. Data are presented as mean ± SEM. (n = 6 /group). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 compared with their respective Control; #p < 0.05, ##p < 0.01, ###p < 0.001, ####p < 0.0001 compared between the 3-NP and 3-NP + OXT groups using one-way analysis of variance (ANOVA) followed by Tukey's multiple comparison test. β-actin is the internal standard

Fig. 6

Effect of OXT on Glutathione (GSH) level in different brain areas in 3-NP administrated male and female rats. a Expression level of the GSH in striatum, hippocampus, prefrontal cortex, and amygdala of male rats and b in the female rats. Data are presented as mean ± SEM. (n = 6/group). **p < 0.01, ***p < 0.001, ****p < 0.0001 compared with their respective Control; #p < 0.05, ##p < 0.01, ###p < 0.001, ####p < 0.0001 compared between the 3-NP or 3-NP-OXT groups using one-way analysis of variance (ANOVA) followed by Tukey's multiple comparison test