Is Forced Swimming Immobility a Good Endpoint for Modeling Negative Symptoms of Schizophrenia? - Study of Sub-Anesthetic Ketamine Repeated Administration Effects

Abstract

Immobility time in the forced swimming has been described as analogous to emotional blunting or apathy and has been used for characterizing schizophrenia animal models. Several clinical studies support the use of NMDA receptor antagonists to model schizophrenia in rodents. Some works describe the effects of ketamine on immobility behavior but there is variability in the experimental design used leading to controversial results. In this study, we evaluated the effects of repeated administration of ketamine subanesthetic doses in forced swimming, locomotion in response to novelty and novel object recognition, aiming a broader evaluation of the usefulness of this experimental approach for modeling schizophrenia in mice. Ketamine (30 mg/kg/day i.p. for 14 days) induced a not persistent decrease in immobility time, detected 24h but not 72h after treatment. This same administration protocol induced a deficit in novel object recognition. No change was observed in mice locomotion. Our results confirm that repeated administration of sub-anesthetic doses of ketamine is useful in modeling schizophrenia-related behavioral changes in mice. However, the immobility time during forced swimming does not seem to be a good endpoint to evaluate the modeling of negative symptoms in NMDAR antagonist animal models of schizophrenia.

Repeated Dosing of Ketamine in the Forced Swim Test: Are Multiple Shots Better Than One?

“…In comparing mice with rats in Table 1 : while studies often used different parameters such as varied dosing and none of the mouse studies used chronic stress, we can conclude that repeated ketamine is capable of producing either decreases or increases in immobility in the FST in both species, under various experimental conditions, with higher doses such 50 or 100 mg/kg favoring immobility. Regarding different strains of mice or rats: the three studies that used CD-1 and CF-1 mice only found decreases in immobility ( 40 – 42 ), whereas studies of other albino mouse strains and C57BL/6J mice showed either increases or decreases in immobility depending on the study parameters and strain used ( 39 , 44 – 48 ). Likewise, Sprague-Dawley or WKY rats were only observed to have decreases in immobility ( 36 , 49 – 51 , 59 , 60 ).…”

“…The table consists of mice and rats of both sexes and various strains, ranging in age from adolescents to adults. The studies primarily used racemic (R,S)-ketamine, although one study (42) as noted in the table only used the (S)-ketamine enantiomer. This table comprises the 24 mice and rat studies from our literature search that used repeated administration of ketamine in the FST.…”

“…For example, studies such as Clarke et al (40) and Neves et al (42), which directly compare in mice a single injection vs. multiple injections at the same dose, suggest that the immobility decreasing effects of repeated ketamine may last longer than those of one injection. Another point is that repeated dosing regimens are capable of producing a decrease in immobility when ketamine is given at different fixed intervals, including less frequently than once a day (40,41,49), exactly once a day (39,42,49,50,52,53,(58)(59)(60), or twice a day (36). In Sprague-Dawley rats weekly administration of ketamine, for 5 weeks at 20 or 50 mg/kg, has previously been shown to induce locomotor sensitization (66).…”

“…The table consists of mice and rats of both sexes and various strains, ranging in age from adolescents to adults. The studies primarily used racemic ( R,S )-ketamine, although one study ( 42 ) as noted in the table only used the ( S )-ketamine enantiomer.…”

“…One of these studies directly compared female Wistar and WKY rats, and found that the latter strain was more responsive to the immobility decreasing effects of this drug ( 59 ). As mentioned above, Neves et al ( 42 ) was the only study in Table 1 that used the enantiomer, ( S )-ketamine. It is noteworthy that this study showed an advantage of repeated over single dose ketamine at 30 mg/kg administered daily for 2 weeks, although the favorable effect of repeated drug did not persist beyond 2 days ( 42 ).…”