Modulation of the endocannabinoid system by (S)-ketamine in an animal model of depression.
Nicole R Silva, Shokouh Arjmand, Luana B Domingos, Adriano M Chaves-Filho, Melina Mottin, Caroline C Real, Anna L Waszkiewicz, Pedro H Gobira, Alessio Nicola Ferraro, Anne M Landau, Carolina H Andrade, Heidi K Müller, Gregers Wegener, Sâmia R L Joca
Pharmacological Research 2025 DOI: 10.1016/j.phrs.2024.107545 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study Peer reviewed |
|---|---|
| Population | Flinders Sensitive Line (FSL) and Flinders Resistant Line (FRL) rats |
| Intervention | S-KET (15 mg/kg) |
| Dose | 15 mg/kg |
| Duration | Acute treatment |
| Topics | Esketamine Depression Ketamine |
| Keywords | Flinders sensitive line Lipidome Ketamine therapy s-ketamine Endocannabinoid system endocannabinoids Cannabinoid signaling Ecb system Moo |
| Citations | 6 |
| Key points | S-ketamine facilitates endocannabinoid signaling in the prefrontal cortex of a rat model of depression, but blocking CB1 receptors does not prevent its antidepressant behavioral effects. |
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 ([3H]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. [3H]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.
Comparable studies
Other preclinical and animal studies on esketamine for depression, most cited first.