Social Isolation-Induced Aggression Potentiates Anxiety and Depressive-Like Behavior in Male Mice Subjected to Unpredictable Chronic Mild Stress

Accumulating epidemiological evidence shows that life event stressors are major vulnerability factors for psychiatric diseases such as major depression. It is also well known that social isolation in male mice results in aggressive behavior. However, it is not known how social isolation-induced aggression affects anxiety and depressive-like behavior in isolated male mice subjected to unpredictable chronic mild stress (CMS), an animal model of depression.C57/B6 male mice were divided into 3 groups; non-stressed controls, in Group I; isolated mice subjected to the CMS protocol in Group II and aggression by physical contact in socially isolated mice subjected to the CMS protocol in Group III. In the sucrose intake test, ingestion of a 1% sucrose solution by mice in Groups II and III was significantly lower than in Group I. Furthermore, intake of this solution in Group III mice was significantly lower than in Group II mice. In the open field test, mice in Group III, showed reduced locomotor activity and reduced entry and retention time in the central zone, compared to Groups I and II mice. Moreover, the distances moved in 1 hour by Group III mice did not differ between night and morning. In the light/black box test, Groups II and III animals spent significantly less time in the light box compared to Group I animals. In the tail suspension test (TST) and forced swimming test (FST), the immobility times of Group II and Group III mice were significantly longer than in Group I mice. In addition, immobility times in the FST were significantly longer in Group III than in Group II mice.These findings show that social isolation-induced aggression could potentiate anxiety and depressive-like behaviors in isolated male mice subjected to CMS

Long-lasting antidepressant action of ketamine, but not glycogen synthase kinase-3 inhibitor SB216763, in the chronic mild stress model of mice.

BackgroundClinical studies demonstrate that the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, induces rapid antidepressant effects in patients with refractive major depressive disorder and bipolar depression. This rapid onset of action makes ketamine a highly attractive drug for patients, particularly those who do not typically respond to therapy. A recent study suggested that glycogen synthase kinase (GSK)-3 may underlie the rapid antidepressant action of ketamine, although the precise mechanisms are unclear. In this study, we examined the effects of ketamine and GSK-3 inhibitor SB216763 in the unpredictable, chronic mild stress (CMS) mouse model of mice.Methodology/principal findingsAdult C57/B6 male mice were divided into 2 groups, a non-stressed control group and the unpredictable CMS (35 days) group. Then, either vehicle, ketamine (10 mg/kg), or the established GSK-3 inhibitor, SB216763 (10 mg/kg), were administered into mice in the CMS group, while vehicle was administered to controls. In the open field test, there was no difference between the four groups (control+vehicle, CMS+vehicle, CMS+ketamine, CMS+SB216763). In the sucrose intake test, a 1% sucrose intake drop, seen in CMS mice, was significantly attenuated after a single dose of ketamine, but not SB216763. In the tail suspension test (TST) and forced swimming test (FST), the increased immobility time seen in CMS mice was significantly attenuated by a single dose of ketamine, but not SB216763. Interestingly, the ketamine-induced increase in the sucrose intake test persisted for 8 days after a single dose of ketamine. Furthermore, a single administration of ketamine, but not SB216763, significantly attenuated the immobility time of the TST and FST in the control (non-stressed) mice.Conclusions/significanceThese findings suggest that a single administration of ketamine, but not GSK-3 inhibitor SB216763, produces a long-lasting antidepressant action in CMS model mice

Prevalence of PTSD and depression among junior middle school students in a rural town far from the epicenter of the Wenchuan earthquake in China.

ContextOn May 12(th) 2008, a devastating earthquake measuring 8.0 on the Richter scale, struck Wenchuan county and surrounding areas in China. The prevalence of mental illness among children and adolescents in a rural town far from the earthquake epicenter is unknown.ObjectiveTo assess the prevalence of posttraumatic stress disorder (PTSD) and depression among junior middle school students in a rural town Ningqiang county, 327 km from the earthquake epicenter.Design, setting, and participantsA population-based mental health survey was conducted in March, 2009.Main outcome measureSurvey Self-designed General Condition Survey Scale, Children's Revised Impact of Event Scale (CRIES-13), and the Depression Self-rating Scale for Children (DSRSC) were used to sample 1,841 junior middle school students in Ningqiang county, ten months after the Wenchuan earthquake.ResultsThe prevalence rate of a high-risk for PTSD was 28.4%, with 32.7% among females, 23.8% among males (female vs. male, pConclusionTraumatic events experienced during the earthquake were significantly associated with symptoms of PTSD and depression in children and adolescents, ten months after the Wenchuan earthquake. These data highlight a need for mental health services for children and adolescents in rural areas, far from earthquake epicenters

Effects of ketamine and the established GSK-3 inhibitor SB216763 in the CMS model.

<p>(<b>A</b>) Locomotion: There were no differences between the four groups. Data show the mean±SEM (n = 8 or 9). (<b>B</b>) Tail-suspension test (TST): The increased immobility time of mice in the CMS groups, decreased significantly 48 hours (day 38) after a single dose of ketamine (10 mg/kg, i.p.), but not SB216763 (10 mg/kg, i.p.). Data show the mean±SEM (n = 5–8). (<b>C</b>) Forced swimming test (FST): The increased immobility time of mice in the CMS groups decreased significantly 48 hours (day 38) after a single dose of ketamine (10 mg/kg, i.p.), but not SB216763 (10 mg/kg, i.p.). Data show the mean±SEM (n = 8 or 9). *p<0.05, **p<0.01 as compared to CMS+Vehicle group.</p

Experimental protocol.

<p>(<b>A</b>): CMS paradigm. CMS procedures were performed for 5-weeks. Drug treatment was performed day 36. The 1% sucrose intake test (SIT) was performed at baseline, days 3, 10, 17, 24, 31, 37, 40, 42 and 44. Vehicle, ketamine (10 mg/kg), or SB216763 (10 mg/kg) were administered at day 36. The open field test (OFT) was performed at day 37. The tail suspension test (TST) and the forced swimming test (FST) was performed at day 38. (<b>B</b>): Acute effects of ketamine and SB216763 in control mice. Vehicle, ketamine (10 mg/kg, i.p.), or SB216763 (2.5, 5.0, or 10 mg/kg, i.p.) were administered into control mice. The behavioral tests, OFT, TST, and FST, were performed 3 and 24 hours after a single administration.</p

Effects of ketamine and the established GSK-3 inhibitor SB216763 in the anhedonia model.

<p>The decreased intake of 1% sucrose in the CMS groups was significantly attenuated 24 hours, 4 days, 6 days and 8 days after a single dose of ketamine (10 mg/kg, i.p.), but not of SB216763 (10 mg/kg, i.p.). Data show the mean±SEM (n = 8 or 9). **p<0.01, ***p<0.001 as compared to Control group.</p

Effects of ketamine and SB216763 on control mice.

<p>Behavioral tests in control mice were performed 3 hours and 24 hours after a single administration of vehicle, ketamine (10 mg/kg, i.p.) or SB216763 (2.5, 5.0, or 10 mg/kg, i.p.). (A): Locomotion: There were no differences between the five groups. Data show the mean±SEM (n = 14–16). (B) Tail-suspension test (TST): There were no differences between the five groups. Data show the mean±SEM (n = 13–16). (C) Forced swimming test (FST): There were no differences between the five groups. Data show the mean±SEM (n = 13–15). (D) Locomotion: There were no differences between the five groups. Data show the mean±SEM (n = 15 or 16). (E) Tail-suspension test (TST): Ketamine significantly (p = 0.001) decreased immobility time, 24 hours after administration. Data show the mean±SEM (n = 15 or 16). (C) Forced swimming test (FST): Ketamine significantly (p = 0.037) decreased immobility time, 24 hours after administration. Data show the mean±SEM (n = 15 or 16). *p<0.05, **p<0.01 as compared with the control group.</p

The correlation matrix of inter-subset for the first-episode drug naive MDD patients.

<p>The correlation matrix of inter-subset for the first-episode drug naive MDD patients.</p