Background and purpose:
We aimed to demonstrate the involvement of 5-HT1A 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.
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-α receptor 1, brain-derived neurotrophic factor (BDNF) and 5-HT1A receptor. N-(2-(4-(2-methoxy-phenyl)-1-piperazin-1-yl)ethyl)-N-(2–pyridyl) cyclohexanecarboxamide (WAY-100635), a 5-HT1A receptor antagonist (0.5 mg·kg−1), was co-administered with cannabidiol. Liver function was evaluated by measuring plasma liver enzymes and bilirubin.
Cannabidiol improved cognition and locomotion, which were impaired by BDL, and restored hippocampal expression of the tumour necrosis factor-α receptor 1 and the BDNF genes, which increased and decreased, respectively, following BDL. It did not affect reduced 5-HT1A expression in BDL mice. All the effects of cannabidiol, except for that on BDNF expression, were blocked by WAY-100635, indicating 5-HT1Areceptor 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-HT1A 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-HT1A receptor expression or liver function. BDNF up-regulation by cannabidiol does not seem to account for the cognitive improvement.
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