Sex and Estrous Cycle Are Not Mediators of S-Ketamine’s Rapid-Antidepressant Behavioral Effects in a Genetic Rat Model of Depression
Shokouh Arjmand, Marie Vadstrup Pedersen, N. Silva, A. Landau, Sâmia R L Joca, Gregers Wegener
International Journal of Neuropsychopharmacology April 17, 2023 DOI: 10.1093/ijnp/pyad016 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Male and female Flinders Sensitive Line (FSL) rats, a genetic model of depression, and Flinders Resistant Line (FRL) rats |
| Intervention | S-ketamine |
| Dose | 20 mg/kg (i.p.) |
| Measures | open field test, forced swim test |
| Topics | Depression Esketamine Ketamine |
| Key findings | S-ketamine at 20 mg/kg produced robust antidepressant-like behavioral effects in the depression-model FSL rats. No sex-specific or estrous cycle phase-specific differences in antidepressant-like response were detected within the study's power, and physiological fluctuations in ovarian sex hormones neither amplified nor diminished ketamine's behavioral antidepressant-like effect or baseline depressive- and anxiety-like behaviors. |
Abstract
Abstract Background Recent preclinical and clinical studies have shed light on the possible impact of sex and estrous/menstrual cycle on ketamine’s antidepressant action but with incongruous results. The preclinical studies that have shown the effects of ovarian sex hormones have not done so in animal models of depression. Thus, the aim of the present study is to scrutinize the acute behavioral responses to a subanesthetic dose of S-ketamine in males vs females and in different estrous phases in free-cycling females in a well-powered translational approach.
Methods: We evaluated the behavioral sensitivity to 20 mg/kg S-ketamine (i.p.) in male and female Flinders Sensitive Line rats (FSLs) and their counterpart Flinders Resistant Line rats (FRLs) subjected to the open field and forced swim tests. Female rats were disaggregated into different estrous phases, and the behavioral outcomes were compared.
Results: Acute administration of S-ketamine had robust antidepressant-like effects in FSLs. Within our study power, we could not detect sex– or estrous cycle–specific different antidepressant-like responses to S-ketamine in FSLs. Fluctuations in the levels of ovarian sex hormones across different estrous cycles did not behaviorally affect S-ketamine’s rapid-acting antidepressant mode of action. No sex-related or estrous cycle–related impact on behavioral despair was observed even among FRLs and saline-treated FSLs.
Conclusions: We conclude that physiological oscillations of estrogen and progesterone levels neither amplify nor diminish the behavioral antidepressant-like effect of S-ketamine. In addition, fluctuations of ovarian sex hormones do not predispose female animals to exhibit enhanced or reduced depressive-like and anxiety-like behaviors.
Comparable studies
Other preclinical and animal studies on esketamine for depression, most cited first.