Repeated Ketamine Exposure Induces an Enduring Resilient Phenotype in Adolescent and Adult Rats

Abstract

Background Major Depressive Disorder (MDD) afflicts up to 10% of adolescents. However, nearly 50% of those afflicted are considered non-responsive to available treatments. Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist has shown potential as a rapid-acting and long-lasting treatment for MDD in adults. Thus, the effectiveness and functional consequences of ketamine exposure during adolescence were explored. Methods Adolescent male rats (postnatal day [PD] 35) received two ketamine (0, 5, 10 or 20 mg/kg) injections, 4 hours apart, after exposure to day 1 of the forced swim test (FST). The next day, rats were re-exposed to the FST to assess ketamine-induced antidepressant-like responses. Separate groups were exposed to chronic unpredictable stress (CUS) to confirm findings from the FST. After these initial experiments, adolescent naïve rats were exposed to either 1 or 15 consecutive days (PD35–49) of ketamine (20 mg/kg) twice/daily. Ketamine's influence on behavioral reactivity to rewarding (i.e., sucrose preference) and aversive (i.e., elevated plus-maze, FST) circumstances was then assessed 2 months after treatment. To control for age-dependent effects, adult rats (PD75–89) were exposed to identical experimental conditions. Results Ketamine (20 mg/kg) reversed the CUS-induced depression-like behaviors in the FST. Repeated ketamine exposure resulted in anxiolytic- and antidepressant-like responses 2 months after drug exposure. None of the ketamine doses used were capable of inducing drug-seeking behaviors as measured by place preference conditioning. Conclusions Repeated ketamine exposure induces enduring resilient-like responses regardless of age of exposure. These findings point to ketamine, and its repeated exposure, as a potentially useful antidepressant during adolescence.

Short‐ and long‐term antidepressant effects of ketamine in a rat chronic unpredictable stress model

“…A related study failed to find any such antidepressant effects of ketamine (Hayase, Yamamoto, & Yamamoto, 2006). However, in that study, rats were forced to swim for an extended period of time, which may have reduced the influence of ketamine on the responses of these rats (Parise et al, 2013).…”

“…The rapid recovery of body weight in stressed rats treated with ketamine suggests that NMDA receptors are involved in modulating feeding behavior during stressful situations. Interestingly, in adult humans and rats, chronic ketamine exposure disrupts appetite and weight gain (Cvrcek, 2008;Parise et al, 2013). Further studies will be necessary to elucidate the possible effects of ketamine when administered at different ages and using different doses/times of injection as well as studies directed at examining the mechanisms of action.…”

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

“…for 10 days in female Wistar Kyoto rats, which is still detectable one week after treatment (Tizabi et al 2012). Parise et al (2013) also reported a decrease in the immobility behavior without effect on locotomotion in animals treated with ketamine 20 mg/kg i.p. twice a day for 15 days.…”

“…The antidepressant effect of sub-anesthetic doses of ketamine has been demonstrated in several studies in mice (Maeng et al 2008, Popik et al 2008, Silva et al 2010, rats (Akinfiresoye and Tizabi 2013, Fraga et al 2013, Garcia et al 2008a, b, 2009, Li et al 2010, Parise et al 2013, Popik et al 2008, Reus et al 2011, Tizabi et al 2012, Yang et al 2012) and humans (Maeng and Zarate 2007, Rot et al 2010, Zarate et al 2006, and the investigation of its mechanism of action or even the involvement of active metabolites is an active field of research (Li et al 2010, Newport et al 2015, Zanos et al 2016). Contrary to our results, there are few works successfully describing the use of ketamine repeated treatment to mimic schizophrenia negative symptoms in the forced swimming.…”

“…Some authors characterized an increase in the immobility as a behavior related to apathy (Chatterjee et al 2011, Chindo et al 2012, Hou et al 2013, while others showed a decrease on this behavior (Akinfiresoye and Tizabi 2013, Garcia et al 2008b, Owolabi et al 2014, Parise et al 2013, Popik et al 2008, Tizabi et al 2012 probably related to the described rapid antidepressant effect of this drug (Rot et al 2010, Zarate et al 2006. In a recent review, Neill et al (2014) discuss this issue and highlight the necessity of more studies to achieve a better understanding of schizophrenia symptoms modeling by NMDAR antagonists using behavioral tasks associated to anhedonia and emotional blunting, especially in mice.…”