TY - JOUR
T1 - Cannabidiol ameliorates cognitive and motor impairments in bile-duct ligated mice via 5-HT 1A receptor activation
AU - Magen, I.
AU - Avraham, Y.
AU - Ackerman, Z.
AU - Vorobiev, L.
AU - Mechoulam, R.
AU - Berry, E. M.
PY - 2010/2
Y1 - 2010/2
N2 - 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.
AB - 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.
KW - Activity
KW - Bile-duct ligation
KW - Cognition
KW - Gene expression
KW - Inflammation
UR - http://www.scopus.com/inward/record.url?scp=77249134168&partnerID=8YFLogxK
U2 - 10.1111/j.1476-5381.2009.00589.x
DO - 10.1111/j.1476-5381.2009.00589.x
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 20128798
AN - SCOPUS:77249134168
SN - 0007-1188
VL - 159
SP - 950
EP - 957
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 4
ER -