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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

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 (15mg/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.

Original languageEnglish
Article number107545
JournalPharmacological Research
Pages (from-to)107545
ISSN1043-6618
DOIs
Publication statusPublished - Jan 2025

Keywords

  • Endocannabinoids
  • Flinders sensitive line
  • Lipidome
  • S-Ketamine

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