Evaluating the role of inhibiting the biosynthesis of estrogens in the sex-specific antidepressant-like effects of ketamine in rats
Sandra Ledesma-Corvi, Jordi Jornet-Plaza, M. Julia García-Fuster
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study |
|---|---|
| Population | Adult Sprague-Dawley rats |
| Interventions | Ketamine Letrozole |
| Dose | 5 mg/kg ketamine, 1 mg/kg letrozole |
| Duration | 7 days ketamine, 8 days letrozole, up to 65 days post-treatment follow-up |
| Topics | Esketamine Ketamine |
| Key points | Ketamine induces an antidepressant-like response in male rats but not in female rats; letrozole produces an antidepressant-like effect in female rats and accelerates ketamine's effect in male rats. |
Abstract
Abstract Ketamine has been recently approved to treat resistant depression; however preclinical studies showed sex differences in its efficacy. Sex steroids, such as estrogen and testosterone, both in the periphery and locally in the brain, are regarded as important modulators of these sex differences. Therefore, the present study evaluated the role of inhibiting estrogen biosynthesis with letrozole, an aromatase inhibitor that catalyzes the conversion of androgen into estrogen, in the differential antidepressant-like-response induced by ketamine with sex. We performed several consecutive studies in adult Sprague-Dawley rats to evaluate potential sex differences in the antidepressant-like effects of ketamine (5 mg/kg, 7 days, i.p.), letrozole (1 mg/kg, 8 days, i.p.) and their combination (letrozole pre-treatment 3 h before ketamine). Acute and repeated antidepressant-like responses were ascertained in a series of behavioral tests (forced-swim, novelty-suppressed feeding, two-bottle choice for sucrose preference). The main results proved clear sex differences in the antidepressant-like response induced by ketamine, which was observed following a repeated paradigm in adult male rats, but rendered inefficacious in female rats. Moreover, decreasing estrogen production with letrozole induced on itself an antidepressant-like response in female rats, while also improved ketamine’s response in male rats (i.e., quicker response, only after a single dose). Interestingly, both the antidepressant-like effects induced by ketamine in male rats or letrozole in female rats persisted over time up to 65 days post-treatment, suggesting long-term sex-directed benefits for these drugs. The present results demonstrated a sex-specific role for inhibiting estrogen biosynthesis in the antidepressant-like response induced by ketamine in male rats. Moreover, letrozole presented itself as a potential antidepressant for females with persistent effects over time. Clearly, estrogen production is key in modulating, in a sex-specific manner, affective-like responses and thus deserve further studies.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 6
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- The use of ketamine as an antidepressant: a systematic review and meta‐analysis Human Psychopharmacology: Clinical and Experimental April 7, 2015
- Role of neurotrophic and growth factors in the rapid and sustained antidepressant actions of ketamine. Neuropharmacology November 17, 2022
- Chronic administration of ketamine elicits antidepressant-like effects in rats without affecting hippocampal brain-derived neurotrophic factor protein levels. Basic & Clinical Pharmacology & Toxicology December 2008
and 1 more in the library