Cannabidiol ameliorates cognitive and motor impairments in bile-duct ligated mice via 5-HT 1A receptor activation

I. Magen*, Y. Avraham, Z. Ackerman, L. Vorobiev, R. Mechoulam, E. M. Berry

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

107 Scopus citations

Abstract

Background and purpose: We aimed to demonstrate the involvement of 5-HT 1A receptors in the therapeutic effect of cannabidiol, a non-psychoactive constituent of Cannabis sativa, in a model of hepatic encephalopathy induced by bile-duct ligation (BDL) in mice. Experimental approach: Cannabidiol (5 mg·kg -1; i.p.) was administered over 4 weeks to BDL mice. Cognition and locomotion were evaluated using the eight-arm maze and the open field tests respectively. Hippocampi were analysed by RT-PCR for expression of the genes for tumour necrosis factor- receptor 1, brain-derived neurotrophic factor (BDNF) and 5-HT 1A receptor. N-(2-(4-(2-methoxy-phenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide (WAY-100635), a 5-HT 1A receptor antagonist (0.5 mg·kg -1), was co-administered with cannabidiol. Liver function was evaluated by measuring plasma liver enzymes and bilirubin. Key results: Cannabidiol improved cognition and locomotion, which were impaired by BDL, and restored hippocampal expression of the tumour necrosis factor- receptor 1 and the BDNF genes, which increased and decreased, respectively, following BDL. It did not affect reduced 5-HT 1A expression in BDL mice. All the effects of cannabidiol, except for that on BDNF expression, were blocked by WAY-100635, indicating 5-HT 1A receptor involvement in cannabidiol's effects. Cannabidiol did not affect the impaired liver function in BDL. Conclusions and implications: The behavioural outcomes of BDL result from both 5-HT 1A receptor down-regulation and neuroinflammation. Cannabidiol reverses these effects through a combination of anti-inflammatory activity and activation of this receptor, leading to improvement of the neurological deficits without affecting 5-HT 1A receptor expression or liver function. BDNF up-regulation by cannabidiol does not seem to account for the cognitive improvement.

Original languageEnglish
Pages (from-to)950-957
Number of pages8
JournalBritish Journal of Pharmacology
Volume159
Issue number4
DOIs
StatePublished - Feb 2010

Keywords

  • Activity
  • Bile-duct ligation
  • Cognition
  • Gene expression
  • Inflammation

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