Modulation of the endocannabinoid system by (S)-ketamine in an animal model of depression
Bibliographic record
Abstract
Ketamine (KET) is recognized as rapid-acting antidepressant, but its mechanisms of action remain elusive. Considering the role of endocannabinoids (eCB) in stress and depression, we investigated if S-KET antidepressant effects involve the regulation of the eCB system using an established rat model of depression based on selective breeding: the Flinders Sensitive Line (FSL) and their controls, the Flinders Resistant Line (FRL). S-KET (15 mg/kg) effects were assessed in rats exposed to the open field and forced swimming test (FST), followed by analysis of the eCB signaling in the rat prefrontal cortex (PFC), a brain region involved in depression neurobiology. Changes in eCB receptors and enzymes were assessed at mRNA and protein levels (qPCR and western blot), CB1 binding ([ 3 H]SR141716A autoradiography) and endocannabinoid content (lipidomics). The results demonstrated that the depressive behavior in FSL was negatively correlated with 2-AG levels, which were restored upon acute S-KET treatment. Although S-KET decreased CB1 and FAAH gene expression in FSL, there were no significant changes at protein levels. [ 3 H]SR141716A binding to CB1 receptors was increased by S-KET and in silico analysis suggested that it binds to CB1, CB2, GPR55 and FAAH. Overall, S-KET effects correlated with an increased endocannabinoid signaling in the PFC, but systemic treatment with rimonabant failed to block its behavioral effects. Altogether, our results indicate that S -KET facilitates eCB signaling in the PFC of FSL. The inability of rimonabant to block the antidepressant effect of S-KET highlights the complexity of its interaction with the ECS, warranting further investigation into the molecular pathways. • FSL rats, a well validated model of depression, presented decreased levels of 2-AG and other major endocannabinoids in the prefrontal cortex (PFC) • S-Ketamine induced rapid antidepressant effects in FSL and attenuated the deficits in 2-AG levels and increased CB1 in the PFC • The behavioral effect of S-Ketamine was associated with an overall upregulation of endocannabinid levels in the PFC • Computational analysis suggested that S-ketamine has a multitargeted action in the endocannabinoid system, which may contribute to its behavioral effects
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.002 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".