Sexually Dimorphic Behavioral Profile in a Transgenic Model Enabling Targeted Recombination in Active Neurons in Response to Ketamine and (2R,6R)-Hydroxynorketamine Administration
David P. Herzog, Ratnadevi M. Mellema, Floortje Remmers, Beat Lutz, Marianne B. Müller, Giulia Treccani
International Journal of Molecular Sciences March 20, 2020 Peer reviewed DOI: 10.3390/ijms21062142 via OpenAlex
Summary
Ketamine and (2R,6R)-hydroxynorketamine exhibit sex-specific differences in behavioral effects in Arc-CreERT2 × CAG-Sun1/sfGFP mice. In the forced swim test, male mice treated with ketamine were less immobile compared to those treated with (2R,6R)-HNK. Additionally, female mice showed an increase in Bdnf mRNA levels after ketamine treatment. These findings highlight distinct behavioral and molecular responses to these treatments based on sex.
Study at a glance
| Design | experimental study |
|---|---|
| Population | Arc-CreERT2 × CAG-Sun1/sfGFP mice |
| Key finding | Male mice treated with ketamine were less immobile than those treated with (2R,6R)-HNK in the forced swim test. |
Abstract
Background: Rapid-acting antidepressants ketamine and (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) have overcome some of the major limitations of classical antidepressants. However, little is known about sex-specific differences in the behavioral and molecular effects of ketamine and (2R,6R)-HNK in rodents. Methods: We treated mice with an intraperitoneal injection of either saline, ketamine (30 mg kg−1) or (2R,6R)-HNK (10 mg kg−1). We performed a comprehensive behavioral test battery to characterize the Arc-CreERT2 × CAG-Sun1/sfGFP mouse line which enables targeted recombination in active populations. We performed a molecular study in Arc-CreERT2 × CAG-Sun1/sfGFP female mice using both immunohistochemistry and in situ hybridization. Results: Arc-CreERT2 × CAG-Sun1/sfGFP mice showed sex differences in sociability and anxiety tests. Moreover, ketamine and (2R,6R)-HNK had opposite effects in the forced swim test (FST) depending on gender. In addition, in male mice, ketamine-treated animals were less immobile compared to (2R,6R)-HNK, thus showing a different profile of the two drugs in the FST. At the molecular level we identified Bdnf mRNA level to be increased after ketamine treatment in female mice. Conclusion: Arc-CreERT2 × CAG-Sun1/sfGFP mice showed sex differences in social and anxiety behavior and a different pattern between ketamine and (2R,6R)-HNK in the FST in male and female mice. At the molecular level, female mice treated with ketamine showed an increase of Bdnf mRNA level, as previously observed in male mice.