Chronic administration of ketamine ameliorates the anxiety- and aggressive-like behavior in adolescent mice induced by neonatal maternal separation

Abstract

Ketamine has long been used as an anesthetic agent. However, ketamine use is associated with numerous side effects, including flashbacks, amnesia, delirium, and aggressive or violent behavior. Ketamine has also been abused as a cocktail with ecstasy, cocaine, and methamphetamine. Several studies have investigated therapeutic applications of ketamine, demonstrating its antidepressant and anxiolytic effects in both humans and rodents. We recently reported that neonatal maternal separation causes enhanced anxiety- and aggressive-like behaviors in adolescent. In the present study, we evaluated how acute and chronic ketamine administration affected the behavioral consequences of neonatal maternal separation in adolescent mice. Litters were separated from dams for 4 hours per day for 19 days beginning after weaning. Upon reaching adolescence (post-natal day 35-49), mice were acutely (single injection) or chronically (7 daily injections) treated with a sub-anesthetic dose (15 mg/kg) of ketamine. At least 1 h after administration of ketamine, mice were subjected to open-field, elevated-plus maze, and resident-intruder tests. We found that acute ketamine treatment reduced locomotor activity. In contrast, chronic ketamine treatment decreased anxiety, as evidenced by increased time spent on open arms in the elevated-plus maze, and remarkably reduced the number and duration of attacks. In conclusion, the present study suggests that ketamine has potential for the treatment of anxiety and aggressive or violent behaviors.

Keywords: Adolescence; Aggression; Anxiety; Ketamine; Maternal separation.

Fig. 1. Experimental timeline for behavioral tests.

Litters were randomly assigned to maternal separation (MS) and handled (HD; control) groups. After the neonatal maternal separation procedure (PND2–20), all litters were weaned at PND22 and then separated according to gender and treatment. Adolescent mice (PND35–49) were administered a single intraperitoneal injection of a sub-anesthetic dose of ketamine (acute treatment) or a daily injection of the same dose for 1 week (chronic treatment). Open-field (OF) and elevated-plus maze (EPM) tests were performed sequentially at each mice (PND42). Resident-intruder test (RIT) was performed at the other mice (PND49). Before RIT, adolescent male mice were isolated in their cages for 2 weeks (PND35–49). At least 1 h after administration of ketamine, mice were subjected to OF, EPM test and RIT.

Fig. 2. Effects of maternal separation on open-field test performance in mice acutely or repeatedly treated with ketamine (15 mg/kg).

(A) Distanced moved and (B) velocity were recorded in an acrylic cage (30 cm²). Results are expressed as means±SEM (HD group, n=23; MS group, n=24; ^**p<0.001 vs. HD+Sal, ^**p<0.001 vs . MS+Sal; one-way ANOVA with Tukey's post hoc test).

Fig. 3. Effects of maternal separation on elevated plus-maze performance in mice acutely or repeatedly treated with ketamine (15 mg/kg).

Anxiety-like behavior was reflected in the percentage of time spent in open arms of the elevated plus maze. Results are expressed as means±SEM (HD group, n=22; MS group, n=26; ^*p<0.05, ^**p<0.001 vs . HD+Sal; ^*p<0.05, ^**p<0.001 vs. MS+Sal; one-way ANOVA followed by Tukey's post hoc test).

Fig. 4. Effects of maternal separation on performance in the resident-intruder test in mice acutely or repeatedly treated with ketamine (15 mg/kg).

Aggressive-like behavior was measured as the latency to first attack (A), number of attacks (B), and cumulative attack duration (C). Results are expressed as means±SEM (HD group, n=21; MS group, n=22; ^*p<0.05 vs . HD+Sal, ^*p<0.05 vs. MS+Sal; one-way ANOVA followed by Tukey's post hoc test).