Cannabidiol ameliorates cognitive and motor impairments in bile-duct ligated mice via 5-HT1A receptor activation.
OBJECTIVE
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.


METHODS
Cannabidiol (5 mg x 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-alpha 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 x kg(-1)), was co-administered with cannabidiol. Liver function was evaluated by measuring plasma liver enzymes and bilirubin.


RESULTS
Cannabidiol improved cognition and locomotion, which were impaired by BDL, and restored hippocampal expression of the tumour necrosis factor-alpha 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
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.
Department of Human Nutrition and Metabolism, Braun School of Public Health, Hebrew University Medical Faculty, Jerusalem, Israel.
I
I
Magen
Y
Y
Avraham
Z
Z
Ackerman
L
L
Vorobiev
R
R
Mechoulam
E M
EM
Berry
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002185:Cannabidiol / Q000494:pharmacology*; D001651:Cholestasis, Extrahepatic / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D003071:Cognition / Q000187:drug effects*; D003135:Common Bile Duct / Q000601:surgery; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000494:pharmacology; D005260:Female; D006501:Hepatic Encephalopathy / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control* / Q000523:psychology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008026:Ligation; D008099:Liver / Q000503:physiopathology; D008111:Liver Function Tests; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D019208:Brain-Derived Neurotrophic Factor; D018492:Dopamine Antagonists; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D017366:Serotonin Receptor Agonists; C506236:Tnfrsf1a protein, mouse; D044282:Receptor, Serotonin, 5-HT1A; D002185:Cannabidiol