C57BL/6N mice show a sub-strain specific resistance to the psychotomimetic effects of ketamine

Abstract

Repeated administration of subanesthetic doses of ketamine is a model of psychosis-like state in rodents. In mice, this treatment produces a range of behavioral deficits, including impairment in social interactions and locomotion. To date, these phenotypes were described primarily in the Swiss and C3H/HeHsd mouse strains. A few studies investigated ketamine-induced behaviors in the C57BL/6J strain, but to our knowledge the C57BL/6N strain was not investigated thus far. This is surprising, as both C57BL/6 sub-strains are widely used in behavioral and neuropsychopharmacological research, and are de facto standards for characterization of drug effects. The goal of this study was to determine if C57BL/6N mice are vulnerable to develop social deficits after 5 days withdrawal from sub-chronic ketamine treatment (5 days, 30 mg/kg, i.p.), an experimental schedule shown before to cause deficits in social interactions in C57BL/6J mice. Our results show that sub-chronic administration of ketamine that was reported to cause psychotic-like behavior in C57BL/6J mice does not induce appreciable behavioral alterations in C57BL/6N mice. Thus, we show that the effects of sub-chronic ketamine treatment in mice are sub-strain specific.

Keywords: C57BL/6 mice; ketamine; locomotion; schizophrenia; social behavior.

FIGURE 1

Treatment schedule and behavioral paradigms. (A) A summary of the treatment schedule. norBNI indicates norbinaltorphimine. (B) A scheme of the partition test. The dotted lines represent a transparent perforated Plexiglas wall. The red box shows the area that was designated as social interaction zone during video analysis. “A” stands for “actor” (subject animal), “P” stands for “partner”. (C) A summary of the open field test. The circles represent wire cups. The red and green rectangles represent, respectively, the social zone and the object zone during video analysis.

FIGURE 2

Locomotor activity during the habituation to the partition and open field tests. (A) Distance traveled during the habituation to the partition apparatus. (B) Activity during habituation to the open field. The group that received only saline is labeled “Sal sal”, ketamine followed by saline “ket sal”, and ketamine followed by norbinaltorphimine “ket norBNI”. Each dot represents an individual mouse. The bar and whiskers correspond to mean and SEM respectively. Group sizes are indicated above the graph.

FIGURE 3

Social interaction in partition test. (A) time to first approach, (B) time spent in social zone, (C) mean distance to partner’s compartment. “Sal sal” corresponds to treatment with saline throughout the procedure, “ket sal” represents subchronic ketamine treatment and then saline injection before the test, and “ket norBNI” is ketamine treatment followed by single injection of norbinaltorphimine. The lines represent the mean and SEM. The numbers above the graphs indicate group sizes.

FIGURE 4

Social interaction in the open field. (A) Time spent in in the half of the cage with the partner mouse under the wire cup. (B) Time spent in the empty-cup zone. (C) Percent time spent in the social zone. (D) Time spent investigating the wire cup containing a partner mouse. (E) Time spent investigating empty cup. (F) Percent time spent investigating social cup. Groups are labeled as follows: “Sal sal” is the control group with only saline injections, “ket sal” corresponds to ketamine treatment and then saline, and “ket norBNI” is ketamine followed by norbinaltorphimine. Results are shown as mean and SEM. The numbers above the graphs indicate group sizes.